Inhibitors of integrin alpha 2 beta 1 and methods of use

ABSTRACT

Disclosed herein, inter alia, are inhibitors of integrin alpha 2 beta 1 and methods of using the same.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/642,553, filed Mar. 13, 2018, which is incorporated herein byreference in its entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant nos.AI077439, HL119893 and HL124049 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND

Severe asthma accounts for approximately 10% of the 300 million peopleworldwide that carry a diagnosis of asthma. These patients havepersistent symptoms of exaggerated airway narrowing despite maximalmedical therapy including anti-inflammatories (inhaled and oralcorticosteroids, leukotriene inhibitors, and antibodies to IgE), andmuscle-targeted therapies (beta-adrenergic agonists). Despite theinitial promise of biologic therapies that target specific cytokinemediators of both T2 high and T2 low asthma, early clinical trials haveshown inconsistent benefit only in a small subset of severe asthmatics.Meanwhile, there have been no significant advances in therapies thatdirectly target airway smooth muscle in over half a century. It is clearthat novel approaches that specifically target smooth muscle arerequired. Currently available muscle-targeted therapies have focused onthe classical actin-myosin machinery contributing to force generation.We recently identified a parallel pathway involved in tensiontransmission from the cell to the extracellular matrix, and found thatdisruption of specific integrin interactions with matrix proteins caneffectively impair tension transmission in airway smooth muscle, acritical step for airway narrowing in asthma.

Asthma is a life-threatening disease affecting approximately 300 millionpeople worldwide and contributing to 250,000 deaths annually (1).Although the phenotypes of allergic asthma are heterogeneous (2), commoncharacteristics include bronchial inflammation, reversible obstruction,and airway hyperreactivity (3). Current therapies for allergic asthmaremain limited (4, 5), despite the increased interest in targetedbiologic therapies over the last two decades. Although promising, thesebiologic therapies have largely been met with limited success inclinical trials. For example, biologics targeting T2 high cytokines suchas IL-13 have failed to show statistically significant reductions inasthma exacerbation rates. In T2 low asthma, numerous clinical trialstargeting TNF-α, IL-17, GM-CSF, and CXCR2 have failed to show eitherconsistent clinical responses or statistically significant benefits. Dueto the fact that biologic therapies offer inhibition of specificcytokine-mediated pathways in asthma, their spectrum of efficacy is muchmore narrow than standard therapies. In addition, they do notnecessarily address all of the clinical objectives of asthma management,necessitating the need for predictive biomarkers for implementation. Inthis setting, therapeutic advances that directly target thehypercontractile airway smooth muscle that results inbronchoconstriction have been notably lacking. Such muscle-specifictherapy would be a particularly attractive therapeutic addition tosevere asthmatics with persistent symptoms as well as those with acuteexacerbations due to hypercontractile smooth muscle. These targetpopulations number in the millions worldwide, and could be clearlyidentified by symptoms alone without the need for an accompanyingbiomarker.

Exaggerated airway narrowing is a central feature of asthma (6), but themechanisms regulating contraction are incompletely understood. It isknown that smooth muscle contraction is driven by calcium-mediatedsignaling to the actin-myosin contractile apparatus, and that forcegeneration is triggered by stimuli such as methacholine or potassiumchloride, enhanced by cytokines such as IL-13 (7) or IL-17A (8, 9), andtransmitted via mediators such as myosin light chain kinase and RhoA.Currently available therapies that target smooth muscle contraction workby inhibiting this core pathway, including beta-adrenergic agonists andmuscarinic antagonists that inhibit upstream of intracellular calciumrelease. Other approaches to inhibit this pathway, such as Rho kinaseinhibitors, often have unacceptable vascular toxicity. Described herein,inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

Herein are provided, inter alia, methods for treating asthma using anα2β1 inhibitor and compositions of α2β1 inhibitors.

In an aspect is provided a compound, or a pharmaceutically acceptablethereof, having the formula:

R¹⁻ is substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. L¹ is a bond or —C(O)—. R² ishydrogen or substituted or unsubstituted alkyl. R³ is hydrogen, halogen,—CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃,—OCH₂X³, —OCHX³ ₂, —CN, —SO_(n3)R^(3D),—SO_(v3)NR^(3A)R^(3B) —NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B),—C(O)R^(3C), —C(O)—OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D),—NR^(3A)SO₂R^(3D), —NR^(3A)C(O)R^(3C), —NR^(3A)C(O)O R^(3C),—NR^(3A)OR^(3C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl. R⁴ ishydrogen or substituted or unsubstituted alkyl. W¹ is O, S, or NR⁸. W²is O, S, or NR⁵. R⁵ is hydrogen or substituted or unsubstituted alkyl.L² is a bond or —C(R⁶)₂—. R⁶ is hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted heteroalkyl. W¹ and R⁶ mayoptionally be joined to form a substituted or unsubstituted 5 to 6membered heterocycloalkyl, or substituted or unsubstituted 5 to 6membered heteroaryl. R⁷ is hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷,—OCX⁷ ₃,—OCH₂X⁷, —OCHX⁷ ₂, —CN, —SO_(n7)R^(7D), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R⁷B, —N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7C),—C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)O R^(7C), —NR^(7A)OR^(7C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. R⁸ is hydrogen or substituted or unsubstitutedalkyl. R^(3A), R^(3B), R^(3C), R^(3D), R^(7A), R^(7B), R^(7C), andR^(7D) are independently hydrogen, —CX₃, —CN, —COON, —CONH₂, —CHX₂,—CH₂X, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl. R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. Each X, X³, and X⁷ are independently —F, —Cl, —Br, or —I. n3and n7 are independently an integer from 0 to 4. m3, m7, v3 and v7 areindependently 1 or 2.

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound described herein.

In an aspect is provided a method of treating asthma, the methodincluding administering to a subject in need thereof an effective amountof an integrin α2β1 inhibitor.

In an aspect is provided a method of treating asthma, the methodincluding administering to a subject in need thereof an effective amountof a compound, or a pharmaceutically acceptable salt thereof, describedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Blockade of integrin α2β1 with C15 inhibits collagen-mediatedadhesion (A, upper) and protects against IL-13 enhanced contraction inmouse tracheal rings (B, lower).

FIG. 2: Intraperitoneal delivery of an inhibitor of integrin α2β1 (C15)to ovalbumin sensitized and challenged mice protects against airwayhyperresponsiveness in vivo (A, upper). Cell adhesion assay of integrinα2β1 (C15) inhibitor. (B, lower).

FIG. 3. (top) Structures of known integrin inhibitors. The commonamidocarboxylic acid is shown. (bottom) Ligand interaction diagram ofC15 with the modelled integrin α2β1 . Key interactions includemetal-carboxylate interaction between magnesium and the compound andbackbone hydrogen bonding between Leu225 and the compound.

FIG. 4. Structure of A2-4 (novel compound) and cell adhesion assay data.

FIG. 5. Select Compounds.

FIG. 6. Cell adhesion assay data using airway smooth muscle cells oncollagen with compound shown.

DETAILED DESCRIPTION

Integrins are present in nearly all multi-cellular organisms and play aconserved role in mediating cell adhesion to fixed extracellular ligandsand in the maintenance of tissue integrity. In invertebrates, asurprisingly small number of integrin heterodimers mediate these diversefunctions. Much has been learned about the critical in vivo functions ofmost members of the integrin family through the use of mice with globalor conditional inactivating mutations of individual subunits and throughthe use of heterodimer-specific blocking monoclonal antibodies.Pharmacological modulation of the α2β1 integrin by compounds describedherein may be used to treat asthma. Described herein are compounds andmethods of use for α2β1 integrin inhibitors.

I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals. The alkyl may include a designated number ofcarbons (e.g., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclizedchain. Examples of saturated hydrocarbon radicals include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—0—). Analkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynylmoiety. An alkyl moiety may be fully saturated. An alkenyl may includemore than one double bond and/or one or more triple bonds in addition tothe one or more double bonds. An alkynyl may include more than onetriple bond and/or one or more double bonds in addition to the one ormore triple bonds.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) maybe placed at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Heteroalkyl is an uncyclized chain. Examples include, but arenot limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety mayinclude one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include two optionally different heteroatoms (e.g., O, N, S, Si, orP). A heteroalkyl moiety may include three optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefour optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P). The term“heteroalkenyl,” by itself or in combination with another term, means,unless otherwise stated, a heteroalkyl including at least one doublebond. A heteroalkenyl may optionally include more than one double bondand/or one or more triple bonds in additional to the one or more doublebonds. The term “heteroalkynyl,” by itself or in combination withanother term, means, unless otherwise stated, a heteroalkyl including atleast one triple bond. A heteroalkynyl may optionally include more thanone triple bond and/or one or more double bonds in additional to the oneor more triple bonds.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂—and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′-represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R¹¹, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R¹¹ or the like, it will be understoodthat the terms heteroalkyl and —NR′R¹¹ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R¹¹ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively. A heterocycloalkyl moiety may include one ring heteroatom(e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include twooptionally different ring heteroatoms (e.g., O, N, S, Si, or P). Aheterocycloalkyl moiety may include three optionally different ringheteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety mayinclude four optionally different ring heteroatoms (e.g., O, N, S, Si,or P). A heterocycloalkyl moiety may include five optionally differentring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moietymay include up to 8 optionally different ring heteroatoms (e.g., O, N,S, Si, or P).

In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or amulticyclic cycloalkyl ring system. In embodiments, monocyclic ringsystems are cyclic hydrocarbon groups containing from 3 to 8 carbonatoms, where such groups can be saturated or unsaturated, but notaromatic. In embodiments, cycloalkyl groups are fully saturated.Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclicrings or fused bicyclic rings. In embodiments, bridged monocyclic ringscontain a monocyclic cycloalkyl ring where two non adjacent carbon atomsof the monocyclic ring are linked by an alkylene bridge of between oneand three additional carbon atoms (i.e., a bridging group of the form(CH₂)_(w) , where w is 1, 2, or 3). Representative examples of bicyclicring systems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fusedbicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ringfused to either a phenyl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. Inembodiments, the bridged or fused bicyclic cycloalkyl is attached to theparent molecular moiety through any carbon atom contained within themonocyclic cycloalkyl ring. In embodiments, cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl isoptionally substituted by one or two groups which are independently oxoor thia. In embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. In embodiments, the multicyclic cycloalkyl is attached tothe parent molecular moiety through any carbon atom contained within thebase ring. In embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl. Examples of multicyclic cycloalkyl groups include, but arenot limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl,and perhydrophenoxazin-1-yl.

In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl”is used in accordance with its plain ordinary meaning. In embodiments, acycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenylring system. In embodiments, monocyclic cycloalkenyl ring systems arecyclic hydrocarbon groups containing from 3 to 8 carbon atoms, wheresuch groups are unsaturated (i.e., containing at least one annularcarbon carbon double bond), but not aromatic. Examples of monocycliccycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. Inembodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings ora fused bicyclic rings. In embodiments, bridged monocyclic rings containa monocyclic cycloalkenyl ring where two non adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge of between one andthree additional carbon atoms (i.e., a bridging group of the form (CH₂),where w is 1, 2, or 3). Representative examples of bicycliccycloalkenyls include, but are not limited to, norbornenyl andbicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenylring systems contain a monocyclic cycloalkenyl ring fused to either aphenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged orfused bicyclic cycloalkenyl is attached to the parent molecular moietythrough any carbon atom contained within the monocyclic cycloalkenylring. In embodiments, cycloalkenyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. Inembodiments, multicyclic cycloalkenyl rings contain a monocycliccycloalkenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two ring systems independently selectedfrom the group consisting of a phenyl, a bicyclic aryl, a monocyclic orbicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclicor bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. Inembodiments, the multicyclic cycloalkenyl is attached to the parentmolecular moiety through any carbon atom contained within the base ring.In embodiments, multicyclic cycloalkenyl rings contain a monocycliccycloalkenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two ring systems independently selectedfrom the group consisting of a phenyl, a monocyclic heteroaryl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl.

In embodiments, a heterocycloalkyl is a heterocyclyl. The term“heterocyclyl” as used herein, means a monocyclic, bicyclic, ormulticyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3,4, 5, 6 or 7 membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S wherethe ring is saturated or unsaturated, but not aromatic. The 3 or 4membered ring contains 1 heteroatom selected from the group consistingof O, N and S. The 5 membered ring can contain zero or one double bondand one, two or three heteroatoms selected from the group consisting ofO, N and S. The 6 or 7 membered ring contains zero, one or two doublebonds and one, two or three heteroatoms selected from the groupconsisting of O, N and S. The heterocyclyl monocyclic heterocycle isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the heterocyclyl monocyclic heterocycle.Representative examples of heterocyclyl monocyclic heterocycles include,but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclylbicyclic heterocycle is a monocyclic heterocycle fused to either aphenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the monocyclicheterocycle portion of the bicyclic ring system. Representative examplesof bicyclic heterocyclyls include, but are not limited to,2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-l-yl,indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. In embodiments, heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl isoptionally substituted by one or two groups which are independently oxoor thia. Multicyclic heterocyclyl ring systems are a monocyclicheterocyclyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. The multicyclic heterocyclyl is attached to the parentmolecular moiety through any carbon atom or nitrogen atom containedwithin the base ring. In embodiments, multicyclic heterocyclyl ringsystems are a monocyclic heterocyclyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ringsystems independently selected from the group consisting of a phenyl, amonocyclic heteroaryl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclicheterocyclyl groups include, but are not limited to10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl,9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl,10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl,12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring.

The term “heteroaryl” refers to aryl groups (or rings) that contain atleast one heteroatom such as N, O,or S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. Thus, the term “heteroaryl” includes fused ring heteroarylgroups (i.e., multiple rings fused together wherein at least one of thefused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylenerefers to two rings fused together, wherein one ring has 5 members andthe other ring has 6 members, and wherein at least one ring is aheteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 6 members, and wherein at least one ring is a heteroaryl ring. And a6,5-fused ring heteroarylene refers to two rings fused together, whereinone ring has 6 members and the other ring has 5 members, and wherein atleast one ring is a heteroaryl ring. A heteroaryl group can be attachedto the remainder of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl,imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl,thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl,benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl,isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. A heteroaryl group substituent may be —O—bonded to a ring heteroatom nitrogen. Non-limiting examples of aryl andheteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl,furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl,thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl,pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl,benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl,pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl,thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl,benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl,diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl,or quinolyl. The examples above may be substituted or unsubstituted anddivalent radicals of each heteroaryl example above are non-limitingexamples of heteroarylene. A heteroaryl moiety may include one ringheteroatom (e.g., O, N, or S). A heteroaryl moiety may include twooptionally different ring heteroatoms (e.g., O, N, or S). A heteroarylmoiety may include three optionally different ring heteroatoms (e.g., O,N, or S). A heteroaryl moiety may include four optionally different ringheteroatoms (e.g., O, N, or S). A heteroaryl moiety may include fiveoptionally different ring heteroatoms (e.g., O, N, or S). An aryl moietymay have a single ring. An aryl moiety may have two optionally differentrings. An aryl moiety may have three optionally different rings. An arylmoiety may have four optionally different rings. A heteroaryl moiety mayhave one ring. A heteroaryl moiety may have two optionally differentrings. A heteroaryl moiety may have three optionally different rings. Aheteroaryl moiety may have four optionally different rings. A heteroarylmoiety may have five optionally different rings.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substituentsdescribed herein.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different.

Individual rings in spirocyclic rings may be substituted orunsubstituted and may have different substituents from other individualrings within a set of spirocyclic rings. Possible substituents forindividual rings within spirocyclic rings are the possible substituentsfor the same ring when not part of spirocyclic rings (e.g. substituentsfor cycloalkyl or heterocycloalkyl rings). Spirocylic rings may besubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heterocycloalkylene and individual ringswithin a spirocyclic ring group may be any of the immediately previouslist, including having all rings of one type (e.g. all rings beingsubstituted heterocycloalkylene wherein each ring may be the same ordifferent substituted heterocycloalkylene). When referring to aspirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃ —SO₃H, —OSO₃H, —SO₂—NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl”,“heterocycloalkyl”, “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R¹¹, —SR′,-halogen, —SiR′R¹¹R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R¹¹, —OC(O)NR′R¹¹, —NR¹¹C(O)R′, —NR′—C(O)NR¹¹R′″, —NR¹¹C(O)₂R′,—NR—C(NR′R¹¹R′″)═NR¹¹″, —NR—C(NR′ R¹¹)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R¹¹, —NRSO₂R′, —NR′NR¹¹R′″, —ONR′R¹¹, —NR′C═(O)NR¹¹NR¹¹′R¹¹″,—CN, —NO₂, in a number ranging from zero to (2m′+1), where m′ is thetotal number of carbon atoms in such radical. R, R′, R¹¹R′″, and R¹¹″each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R¹¹, R′″,and R¹¹″ group when more than one of these groups is present. When R′and R¹¹ are attached to the same nitrogen atom, they can be combinedwith the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. Forexample, —NR′R¹¹ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R¹¹, —SR′, -halogen, —SiR′R¹¹R′′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R¹¹, —OC(O)NR′R¹¹, —NR¹¹C(O)R′,—NR′—C(O)NR¹¹R″′, —NR¹¹C(O)₂R′, —NR—C(NR′R¹¹R′″)═NR¹¹″,—NR—C(NR′R¹¹)═NR¹¹′, —S(O)R′, —S(O)₂R′, —S(O)₂NRIR¹¹, —NRSO₂R′,—NR′NR¹¹R¹¹′, —ONR′R¹¹, —NR′C═(O)NR¹¹NR¹¹′R¹¹″, —CN, —NO₂, —R′, —N3,—CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R¹¹, R′″, and R¹¹″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound of the invention includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R¹¹, R¹¹′, and R¹¹″ groups when more than one of thesegroups is present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)——X—(C″R¹¹R¹¹′)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R¹¹, and R¹¹′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CCl₃, —CBr₃, —CF_(3,) —CI_(13,) —CHCl_(2,)        —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃ H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,        —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHC₁₂, —OCH Br₂, —OCHI₂,        —OCHF₂, —OCH₂C₁, —OCH₂Br, —OCH₂I, —OCH₂F, —N_(3,) unsubstituted        alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),        unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2        to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),        unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆        cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl        (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered        heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),        unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or        unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5        to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,            —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SO ₃H, —SO₄H, —SO₂NH₂, —NHNH₂,            —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,            —NHC(O)OH, —NHOH, —OCC13, —OCF₃, —OCBr3, —OCI3,—OCHCl_(2,)            —OC HBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F,            —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or            C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8            membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4            membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈            cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl), and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,                —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl , —CH₂Br, —CH₂F, —CH₂I,                —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,                —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —O CHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,                —OCH₂Cl, ——OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted                alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),                unsubstituted heteroalkyl (e.g., 2 to 8 membered                heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4                membered heteroalkyl), unsubstituted cycloalkyl (e.g.,                C₃-C₈ cycloalkyl, C₃-₆ cycloalkyl, or C₅-C₆ cycloalkyl),                unsubstituted heterocycloalkyl (e.g., 3 to 8 membered                heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5                to 6 membered heterocycloalkyl), unsubstituted aryl                (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 10 membered                heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6                membered heteroaryl), and        -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,            —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,            —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO ₃H, —SO₄H,            —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,            —NHC(O)H, —NHC(O)OH, —NHOH, —OCCL₃, —OCF₃, —OC Br₃, —OCI₃,            —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,            —O CH₂F, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₅-C₆            alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2            to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2            to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.,            C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl).

A “size-limited substituent” or “ size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “ lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₁₀ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

In embodiments, a substituted or unsubstituted moiety (e.g., substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, and/orsubstituted or unsubstituted heteroarylene) is unsubstituted (e.g., isan unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, unsubstituted alkylene, unsubstitutedheteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted arylene, and/or unsubstitutedheteroarylene, respectively). In embodiments, a substituted orunsubstituted moiety (e.g., substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, and/or substituted or unsubstituted heteroarylene) issubstituted (e.g., is a substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkyl ene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene, respectively).

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted aryl ene, and/orsubstituted heteroarylene) is substituted with at least one substituentgroup, wherein if the substituted moiety is substituted with a pluralityof substituent groups, each substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of sub stituent groups, each sub stituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted aryl ene, and/orsubstituted heteroarylene) is substituted with at least one size-limitedsubstituent group, wherein if the substituted moiety is substituted witha plurality of size-limited substituent groups, each size-limitedsubstituent group may optionally be different. In embodiments, if thesubstituted moiety is substituted with a plurality of size-limitedsubstituent groups, each size-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one lower substituent group,wherein if the substituted moiety is substituted with a plurality oflower substituent groups, each lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of lower substituent groups, each lower substituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groupsselected from substituent groups, size-limited substituent groups, andlower substituent groups; each substituent group, size-limitedsubstituent group, and/or lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent group isdifferent.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolysulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present disclosure containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present disclosure. Salts tend to be more solublein aqueous or other protonic solvents than are the corresponding freebase forms. In other cases, the preparation may be a lyophilized powderin 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH rangeof 4.5 to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present disclosure may exist as salts, suchas with pharmaceutically acceptable acids. The present disclosureincludes such salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Provided herein are agents (e.g. compounds, drugs, therapeutic agents)that may be in a prodrug form. Prodrugs of the compounds describedherein are those compounds that readily undergo chemical changes underselect physiological conditions to provide the final agents (e.g.compounds, drugs, therapeutic agents). Additionally, prodrugs can beconverted to agents (e.g. compounds, drugs, therapeutic agents) bychemical or biochemical methods in an ex vivo environment. Prodrugsdescribed herein include compounds that readily undergo chemical changesunder select physiological conditions to provide agents (e.g. compounds,drugs, therapeutic agents) to a biological system (e.g. in a subject, ina cancer cell, in the extracellular space near a cancer cell).

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as(R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomersare encompassed within the scope of the present invention. The compoundsof the present invention do not include those which are known in the artto be too unstable to synthesize and/or isolate. The present inventionis meant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of thedisclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵1), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in

Markush groups, for example, each amino acid position that contains morethan one possible amino acid. It is specifically contemplated that eachmember of the Markush group should be considered separately, therebycomprising another embodiment, and the Markush group is not to be readas a single unit.

As used herein, the term “bioconjugate reactive moiety” and“bioconjugate reactive group” refers to a moiety or group capable offorming a bioconjugate (e.g., covalent linker) as a result of theassociation between atoms or molecules of bioconjugate reactive groups.The association can be direct or indirect. For example, a conjugatebetween a first bioconjugate reactive group (e.g., —NH₂, —COOH,—N-hydroxysuccinimide, or maleimide) and a second bioconjugate reactivegroup (e.g., sulfhydryl, sulfur-containing amino acid, amine, aminesidechain containing amino acid, or carboxylate) provided herein can bedirect, e.g., by covalent bond or linker (e.g. a first linker of secondlinker), or indirect, e.g., by non-covalent bond (e.g. electrostaticinteractions (e.g. ionic bond, hydrogen bond, halogen bond), van derWaals interactions (e.g. dipole-dipole, dipole-induced dipole, Londondispersion), ring stacking (pi effects), hydrophobic interactions andthe like). In embodiments, bioconjugates or bioconjugate linkers areformed using bioconjugate chemistry (i.e. the association of twobioconjugate reactive groups) including, but are not limited tonucleophilic substitutions (e.g., reactions of amines and alcohols withacyl halides, active esters), electrophilic substitutions (e.g., enaminereactions) and additions to carbon-carbon and carbon-heteroatom multiplebonds (e.g., Michael reaction, Diels-Alder addition). These and otheruseful reactions are discussed in, for example, March, ADVANCED ORGANICCHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney etal., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198,American Chemical Society, Washington, D.C., 1982. In embodiments, thefirst bioconjugate reactive group (e.g., maleimide moiety) is covalentlyattached to the second bioconjugate reactive group (e.g. a sulfhydryl).In embodiments, the first bioconjugate reactive group (e.g., haloacetylmoiety) is covalently attached to the second bioconjugate reactive group(e.g. a sulfhydryl). In embodiments, the first bioconjugate reactivegroup (e.g., pyridyl moiety) is covalently attached to the secondbioconjugate reactive group (e.g. a sulfhydryl). In embodiments, thefirst bioconjugate reactive group (e.g., N-hydroxysuccinimide moiety) iscovalently attached to the second bioconjugate reactive group (e.g. anamine). In embodiments, the first bioconjugate reactive group (e.g.,maleimide moiety) is covalently attached to the second bioconjugatereactive group (e.g. a sulfhydryl). In embodiments, the firstbioconjugate reactive group (e.g., sulfoN-hydroxysuccinimide moiety) iscovalently attached to the second bioconjugate reactive group (e.g. anamine).

Useful bioconjugate reactive moieties used for bioconjugate chemistriesherein include, for example:

(a) carboxyl groups and various derivatives thereof including, but notlimited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters,acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl,alkenyl, alkynyl and aromatic esters;

(b) hydroxyl groups which can be converted to esters, ethers, aldehydes,etc.

(c) haloalkyl groups wherein the halide can be later displaced with anucleophilic group such as, for example, an amine, a carboxylate anion,thiol anion, carbanion, or an alkoxide ion, thereby resulting in thecovalent attachment of a new group at the site of the halogen atom;

(d) dienophile groups which are capable of participating in Diels-Alderreactions such as, for example, maleimido or maleimide groups;

(e) aldehyde or ketone groups such that subsequent derivatization ispossible via formation of carbonyl derivatives such as, for example,imines, hydrazones, semicarbazones or oximes, or via such mechanisms asGrignard addition or alkyllithium addition;

(f) sulfonyl halide groups for subsequent reaction with amines, forexample, to form sulfonamides;

(g) thiol groups, which can be converted to disulfides, reacted withacyl halides, or bonded to metals such as gold, or react withmaleimides;

(h) amine or sulfhydryl groups (e.g., present in cysteine), which canbe, for example, acylated, alkylated or oxidized;

(i) alkenes, which can undergo, for example, cycloadditions, acylation,Michael addition, etc;

(j) epoxides, which can react with, for example, amines and hydroxylcompounds;

(k) phosphoramidites and other standard functional groups useful innucleic acid synthesis;

(l) metal silicon oxide bonding; and

(m) metal bonding to reactive phosphorus groups (e.g. phosphines) toform, for example, phosphate diester bonds.

(n) azides coupled to alkynes using copper catalyzed cycloaddition clickchemistry.

(o) biotin conjugate can react with avidin or strepavidin to form aavidin-biotin complex or streptavidin-biotin complex.

The bioconjugate reactive groups can be chosen such that they do notparticipate in, or interfere with, the chemical stability of theconjugate described herein. Alternatively, a reactive functional groupcan be protected from participating in the crosslinking reaction by thepresence of a protecting group. In embodiments, the bioconjugatecomprises a molecular entity derived from the reaction of an unsaturatedbond, such as a maleimide, and a sulfhydryl group.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

An “α2β1-inhibitor” or “α2β1 inhibitor” as used herein refers to asubstance, agent, or composition (e.g. a compound, nucleic acid,polynucleotide, peptide, protein, or antibody) capable of reducing theactivity of α2β1 integrin when compared to a control compound (e.g.known to have no reduction in α2β1 integrin activity) or the absence ofthe α2β1-inhibitor compound. An “α2β1-inhibitor compound” or “α2β1inhibitor compound” refers to a compound (e.g. compound describedherein) that reduce the activity of α2β1 integrin when compared to acontrol, such as absence of the compound or a compound with knowninactivity. An “α2β1-inhibitor-antibody” or “α2β1 inhibitor-antibody”refers to an antibody that reduces the activity of α2β1 integrin whencompared to a control (e.g. the absence of the antibody). An“α2β1-inhibitor-RGD peptide” or “α2β1inhibitor-RGD peptide” refers to aRGD-peptide that reduces the activity of α2β1 integrin when compared toa control (e.g. the absence of the peptide).

“Specific,” “specifically”, “specificity”, or the like of a composition(e.g. a compound, nucleic acid, polynucleotide, peptide, protein, orantibody) refers to the composition's ability to discriminate betweenparticular molecular targets to a significantly greater extent thanother proteins in the cell (e.g. a compound having specificity towardsα2β1 integrin binds to α2β1 integrin whereas the same compound displayslittle-to-no binding to other integrins such as αvβ1, α8β1, α5β1, αvβ3,αvβ5, or αvβ6). An “α2β1-specific compound” or “α2β1 specific compound”refers to a compound (e.g. compounds described herein) havingspecificity towards α2β1 integrin. An “α2β1-specific antibody” or “α2β1specific antibody” refers to an antibody having specificity towards α2β1integrin. An “α2β1-specific RGD peptide” or “α2β1 specific RGD peptide”refers to a RGD peptide having specificity towards α2β1 integrin.

The terms “selective,” or “selectivity” or the like of a compound refersto the composition's (e.g. a compound, nucleic acid, polynucleotide,peptide, protein, or antibody) ability to cause a particular action in aparticular molecular target (e.g. a compound having selectivity towardα2β1 integrin would inhibit only α2β1 . An “α2β1-selective compound” or“α2β1 selective compound” refers to a compound (e.g. compounds describedherein) having selectivity towards α2β1 integrin. An “α2β1-selectiveantibody” or “α2β1 selective antibody” refers to an antibody havingselectivity towards α2β1 integrin. An “α2β1-selective RGD peptide” or“α2β1 selective RGD peptide” refers to a RGD peptide having selectivitytowards α2β1 integrin.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues,wherein the polymer may optionally be conjugated to a moiety that doesnot consist of amino acids. The terms apply to amino acid polymers inwhich one or more amino acid residue is an artificial chemical mimeticof a corresponding naturally occurring amino acid, as well as tonaturally occurring amino acid polymers and non-naturally occurringamino acid polymer.

A polypeptide, or a cell is “recombinant” when it is artificial orengineered, or derived from or contains an artificial or engineeredprotein or nucleic acid (e.g. non-natural or not wild type). Forexample, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, suchthat it is not associated with nucleotide sequences that normally flankthe polynucleotide as it is found in nature is a recombinantpolynucleotide. A protein expressed in vitro or in vivo from arecombinant polynucleotide is an example of a recombinant polypeptide.Likewise, a polynucleotide sequence that does not appear in nature, forexample a variant of a naturally occurring gene, is recombinant.

“RGD peptide” as used herein refers to a tripeptide comprising Arg, Gly,and Asp. RGD peptides typically act as recognition sequences forintegrins and in some embodiments, promote cellular adhesion viaintegrin binding. RGD peptides as used herein refers to naturallyoccurring RGD sequences, RGD mimetics (e.g. substitutions of R, G, or Dwith non-proteinogenic amino acids), RGD peptides covalently bound to atargeting-moiety (e.g. a molecule for targeting the peptide to aspecific integrin or specific location in a cell or organism), andcyclized RGD peptides of embodiments described herein. Exemplary RGDpeptides include Arg-Gly-Asp, Asp-Gly-Arg,cyclo-Gly-Arg-Gly-Asp-Ser-Pro, and KGD peptides includeCys-Asn-Thr-Leu-Lys-Gly-Asp-Cys and Asn-Thr-Leu-Lys-Gly-Asp, and thosefound in Ann. Rev. Cell & Dev. Biol., 1996, Nov., Vol. 12: 697-715 andProteins, 1992 December;14(4): 509-15.

“Antibody” refers to a polypeptide comprising a framework region from animmunoglobulin gene or fragments thereof that specifically binds andrecognizes an antigen. The recognized immunoglobulin genes include thekappa, lambda, alpha, gamma, delta, epsilon, and mu constant regiongenes, as well as the myriad immunoglobulin variable region genes. Lightchains are classified as either kappa or lambda. Heavy chains areclassified as gamma, mu, alpha, delta, or epsilon, which in turn definethe immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.Typically, the antigen-binding region of an antibody will be mostcritical in specificity and affinity of binding.

An exemplary immunoglobulin (antibody) structural unit comprises atetramer. Each tetramer is composed of two identical pairs ofpolypeptide chains, each pair having one “light” (about 25 kD) and one“heavy” chain (about 50-70 kD). The N-terminus of each chain defines avariable region of about 100 to 110 or more amino acids primarilyresponsible for antigen recognition. The terms variable light chain(V_(L)) and variable heavy chain (V_(H)) refer to these light and heavychains respectively.

Antibodies exist, e.g., as intact immunoglobulins or as a number ofwell-characterized fragments produced by digestion with variouspeptidases. Thus, for example, pepsin digests an antibody below thedisulfide linkages in the hinge region to produce F(ab)′₂, a dimer ofFab which itself is a light chain joined to V_(H)-C_(H)l by a disulfidebond. The F(ab)′₂ may be reduced under mild conditions to break thedisulfide linkage in the hinge region, thereby converting the F(ab)′₂dimer into an Fab′ monomer. The Fab′ monomer is essentially Fab withpart of the hinge region (see Fundamental Immunology (Paul ed., 3d ed.1993). While various antibody fragments are defined in terms of thedigestion of an intact antibody, one of skill will appreciate that suchfragments may be synthesized de novo either chemically or by usingrecombinant DNA methodology. Thus, the term antibody, as used herein,also includes antibody fragments either produced by the modification ofwhole antibodies, or those synthesized de novo using recombinant DNAmethodologies (e.g., single chain Fv) or those identified using phagedisplay libraries (see, e.g., McCafferty et al., Nature 348:552-554(1990)).

For preparation of suitable antibodies of the invention and for useaccording to the invention, e.g., recombinant, monoclonal, or polyclonalantibodies, many techniques known in the art can be used (see, e.g.,Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., ImmunologyToday 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies andCancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols inImmunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual(1988); and Goding, Monoclonal Antibodies: Principles and Practice (2ded. 1986)). The genes encoding the heavy and light chains of an antibodyof interest can be cloned from a cell, e.g., the genes encoding amonoclonal antibody can be cloned from a hybridoma and used to produce arecombinant monoclonal antibody. Gene libraries encoding heavy and lightchains of monoclonal antibodies can also be made from hybridoma orplasma cells. Random combinations of the heavy and light chain geneproducts generate a large pool of antibodies with different antigenicspecificity (see, e.g., Kuby, Immunology (3^(rd) ed. 1997)). Techniquesfor the production of single chain antibodies or recombinant antibodies(U.S. Pat. Nos, 4,946,778, 4,816,567) can be adapted to produceantibodies to polypeptides of this invention. Also, transgenic mice, orother organisms such as other mammals, may be used to express humanizedor human antibodies (see, e.g., U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio/Technology10:779-783 (1992); Lonberg etal., Nature 368:856-859 (1994); Morrison,Nature 368:812-13 (1994); Fishwild etal., Nature Biotechnology 14:845-51(1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg &Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phagedisplay technology can be used to identify antibodies and heteromericFab fragments that specifically bind to selected antigens (see, e.g.,McCafferty etal., Nature 348:552-554 (1990); Marks et al., Biotechnology10:779-783 (1992)). Antibodies can also be made bispecific, i.e., ableto recognize two different antigens (see, e.g., WO 93/08829, Trauneckeret al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods inEnzymology 121:210 (1986)). Antibodies can also be heteroconjugates,e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S.Pat. No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).

Methods for humanizing or primatizing non-human antibodies are wellknown in the art. Generally, a humanized antibody has one or more aminoacid residues introduced into it from a source which is non-human. Thesenon-human amino acid residues are often referred to as import residues,which are typically taken from an import variable domain. Humanizationcan be essentially performed following the method of Winter andco-workers (see, e.g., Jones et al., Nature 321:522-525 (1986);Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science239:1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596(1992)), by substituting rodent CDRs or CDR sequences for thecorresponding sequences of a human antibody. Accordingly, such humanizedantibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), whereinsubstantially less than an intact human variable domain has beensubstituted by the corresponding sequence from a non-human species. Inpractice, humanized antibodies are typically human antibodies in whichsome CDR residues and possibly some FR residues are substituted byresidues from analogous sites in rodent antibodies.

A “chimeric antibody” is an antibody molecule in which (a) the constantregion, or a portion thereof, is altered, replaced or exchanged so thatthe antigen binding site (variable region) is linked to a constantregion of a different or altered class, effector function and/orspecies, or an entirely different molecule which confers new propertiesto the chimeric antibody, e.g., an enzyme, toxin, hormone, growthfactor, drug, etc.; or (b) the variable region, or a portion thereof, isaltered, replaced or exchanged with a variable region having a differentor altered antigen specificity. The preferred antibodies of, and for useaccording to the invention include humanized and/or chimeric monoclonalantibodies.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein refers to conversion of a proteininto a biologically active derivative from an initial inactive ordeactivated state. The terms reference activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein decreased in a disease.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition refers meansnegatively affecting (e.g. decreasing) the concentration or levels ofthe protein relative to the concentration or level of the protein in theabsence of the inhibitor. In embodiments inhibition refers to reductionof a disease or symptoms of disease. In embodiments, inhibition refersto a reduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g. an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g. aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation).

“Patient” or “subject in need thereof” or “subject” refers to a livingorganism suffering from or prone to a disease or condition that can betreated by administration of a compound or pharmaceutical composition orby a method, as provided herein. Non-limiting examples include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In some embodiments, a patient ishuman. In some embodiments, a subject is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is asthma. The disease may be airwayhyperresponsiveness. The disease may be airway hyperresponsiveness inasthma. The disease may be angiogenesis. The disease may be anautoimmune disease (e.g., scleroderma, lupus, diabetes, or rheumatoidarthritis). The disease may be an inflammatory disease (e.g., autoimmunediseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenileidiopathic arthritis, multiple sclerosis, systemic lupus erythematosus(SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitustype 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto' sthyroiditi s, ankylosing spondyliti s, psoriasi s, Sjogren'ssyndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis,Behcet's disease, Crohn' s disease, ulcerative colitis, bullouspemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatorybowel disease, Addison's disease, Vitiligo,asthma, allergic asthma, acnevulgaris, celiac disease, chronic prostatitis, inflammatory boweldisease, pelvic inflammatory disease, reperfusion injury, sarcoidosis,transplant rejection, interstitial cystitis, atherosclerosis,scleroderma, or atopic dermatitis).

As used herein, the term “inflammatory disease” refers to a disease orcondition characterized by aberrant inflammation (e.g. an increasedlevel of inflammation compared to a control such as a healthy person notsuffering from a disease). Examples of inflammatory diseases includeautoimmune diseases, arthritis, rheumatoid arthritis, psoriaticarthritis, juvenile idiopathic arthritis, multiple sclerosis, systemiclupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes,diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto'sencephalitis, Hashimoto's thyroiditis, ankylosing spondylitis,psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis,auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease,Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronicprostatitis, inflammatory bowel disease, pelvic inflammatory disease,reperfusion injury, sarcoidosis, transplant rejection, interstitialcystitis, atherosclerosis, scleroderma, and atopic dermatitis.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity, aberrant refers to activity that isgreater or less than a normal control or the average of normalnon-diseased control samples. Aberrant activity may refer to an amountof activity that results in a disease, wherein returning the aberrantactivity to a normal or non-disease-associated amount (e.g. byadministering a compound or using a method as described herein), resultsin reduction of the disease or one or more disease symptoms.

A “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist. The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,intraperitoneal, intramuscular, intralesional, intrathecal, intranasalor subcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route, including parenteral and transmucosal (e.g., buccal,sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal)compatible with the preparation. Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

“Co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of theinvention can be administered alone or can be coadministered to thepatient. Coadministration is meant to include simultaneous or sequentialadministration of the compounds individually or in combination (morethan one compound). Thus, the preparations can also be combined, whendesired, with other active substances (e.g. to reduce metabolicdegradation). The compositions of the present invention can be deliveredtransdermally, by a topical route, or formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alfa, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., reducing, eliminating, or slowing theprogression of disease symptoms (e.g. symptoms of asthma). Determinationof a therapeutically effective amount of a compound of the invention iswell within the capabilities of those skilled in the art, especially inlight of the detailed disclosure herein.

As used herein “asthma” refers to any disease or condition characterizedby inflammation within the circulatory system, often accompanied withwheezing, airway restriction, shortness of breath, chest tightness, andcoughing. In embodiments, asthma is characterized by airwayhyperresponsiveness. In embodiments, asthma is airwayhyperresponsiveness. Asthma may refer inflammation in the bronchi andbronchioles. Asthma may refer to atopic asthma. Asthma may refer tonon-atopic asthma.

The compounds described herein (e.g., compound wherein R³ is nothydrogen) may be prodrugs. The term “prodrug” when referring to aprodrug described herein (e.g. α2β1-inhibitor compound moiety bonded toa prodrug moiety) refers to the compound including the α2β1-inhibitorcompound moiety and the prodrug moiety. A “prodrug moiety” is theportion of a prodrug that may be cleaved from the prodrug resulting inan increased activity of the non-prodrug moiety portion of the prodrug,for example an α2β1-inhibitor compound having increased α2β1-inhibitoractivity relative to the prodrug of the α2β1-inhibitor compound. Inembodiments, the compounds described herein are prodrugs, wherein theprodrug moiety is the component of the compound that is not anα2β1-inhibitor compound moiety and is released from the α2β1-inhibitorcompound moiety upon degradation of the prodrug.

In embodiments, degradation of the prodrug includes cleavage of —OR³,wherein R³ is not hydrogen. In embodiments, degradation of the prodrugincludes cleavage of R³, wherein R³ is not hydrogen. In embodiments, anα2β1-inhibitor compound is a compound described herein wherein R³ ishydrogen and a prodrug of the α2β1-inhibitor compound is the identicalcompound except R³ is not a hydrogen. A person having ordinary skill inthe art would understand that the α2β1-inhibitor compound moietyincludes only those compounds compatible with the chemistry providedherein for connecting the α2β1-inhibitor compound moiety to the prodrugmoiety and for release of the α2β1-inhibitor compound from the compound(prodrug) (e.g., in vivo). In embodiments, degradation of the prodrugreleases an active agent (e.g., α2β1-inhibitor compound). In suchcompounds, the resulting active agent includes a higher level ofactivity compared to the level of activity of the intact prodrug. Inembodiments, degradation of the prodrug includes cleavage of —OR³,wherein R³ is not hydrogen, by an esterase or amidase and replacement of—OR³ with —OH or the corresponding anionic moiety.

Integrins are transmembrane proteins that mediate interactions betweenadhesion molecules on adjacent cells and/or the extracellular matrix(ECM). Integrins have diverse roles in several biological processesincluding, for example, cell migration during development and woundhealing, cell differentiation, and apoptosis. Integrins typically existas heterodimers consisting of a subunits (about 120-170 kDa in size) andβ subunits (about 90-100 kDa in size).

The terms “α2β1” and “α2β1 integrin” refer to an integrin comprised ofα2 subunit and a β1 subunit and is used according to its common,ordinary meaning. “α2β1” refers to proteins of the same or similarnames, homologs, isoforms, and functional fragments thereof, so long assuch fragments retain α2β1 integrin activity. The term includes anyrecombinant or naturally-occurring form of α2β1, or an α2β1 preprotein,or variants thereof that maintain α2β1 activity (e.g. within at least30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared towildtype α2β1). In embodiments, α2 has the protein sequencecorresponding to RefSeq NP_002194.2. In embodiments, α2 has the proteinsequence corresponding to the proteolytically processed mature versionof RefSeq NP_002194.2. In embodiments, α2 has the amino acid sequencecorresponding to nucleic acid sequence of the reference numberNM_002203.3. In embodiments, β1 has the protein sequence correspondingto RefSeq NP_002202.2 In embodiments, β1 has the amino acid sequencecorresponding to the reference number GI: 19743813.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs and amino acid mimetics thatfunction in a manner similar to the naturally occurring amino acids.Naturally occurring amino acids are those encoded by the genetic code,as well as those amino acids that are later modified, e.g.,hydroxyproline, y-carboxyglutamate, and O-phosphoserine. Amino acidanalogs refers to compounds that have the same basic chemical structureas a naturally occurring amino acid, i.e., an a carbon that is bound toa hydrogen, a carboxyl group, an amino group, and an R group, e.g.,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) ormodified peptide backbones, but retain the same basic chemical structureas a naturally occurring amino acid. Amino acid mimetics refers tochemical compounds that have a structure that is different from thegeneral chemical structure of an amino acid, but that functions in amanner similar to a naturally occurring amino acid. The terms“non-naturally occurring amino acid” and “unnatural amino acid” refer toamino acid analogs, synthetic amino acids, and amino acid mimetics whichare not found in nature.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise,may be referred to by their commonly accepted single-letter codes.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues,wherein the polymer may in embodiments be conjugated to a moiety thatdoes not consist of amino acids. The terms apply to amino acid polymersin which one or more amino acid residue is an artificial chemicalmimetic of a corresponding naturally occurring amino acid, as well as tonaturally occurring amino acid polymers and non-naturally occurringamino acid polymers. A “fusion protein” refers to a chimeric proteinencoding two or more separate protein sequences that are recombinantlyexpressed as a single moiety.

As may be used herein, the terms “nucleic acid,” “nucleic acidmolecule,” “nucleic acid oligomer,” “oligonucleotide,” “nucleic acidsequence,” “nucleic acid fragment” and “polynucleotide” are usedinterchangeably and are intended to include, but are not limited to, apolymeric form of nucleotides covalently linked together that may havevarious lengths, either deoxyribonucleotides or ribonucleotides, oranalogs, derivatives or modifications thereof. Different polynucleotidesmay have different three-dimensional structures, and may perform variousfunctions, known or unknown. Non-limiting examples of polynucleotidesinclude a gene, a gene fragment, an exon, an intron, intergenic DNA(including, without limitation, heterochromatic DNA), messenger RNA(mRNA), transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinantpolynucleotide, a branched polynucleotide, a plasmid, a vector, isolatedDNA of a sequence, isolated RNA of a sequence, a nucleic acid probe, anda primer. Polynucleotides useful in the methods of the disclosure maycomprise natural nucleic acid sequences and variants thereof, artificialnucleic acid sequences, or a combination of such sequences.

A polynucleotide is typically composed of a specific sequence of fournucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine(T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus,the term “polynucleotide sequence” is the alphabetical representation ofa polynucleotide molecule; alternatively, the term may be applied to thepolynucleotide molecule itself. This alphabetical representation can beinput into databases in a computer having a central processing unit andused for bioinformatics applications such as functional genomics andhomology searching. Polynucleotides may optionally include one or morenon-standard nucleotide(s), nucleotide analog(s) and/or modifiednucleotides.

“Conservatively modified variants” applies to both amino acid andnucleic acid sequences. With respect to particular nucleic acidsequences, “conservatively modified variants” refers to those nucleicacids that encode identical or essentially identical amino acidsequences. Because of the degeneracy of the genetic code, a number ofnucleic acid sequences will encode any given protein. For instance, thecodons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, atevery position where an alanine is specified by a codon, the codon canbe altered to any of the corresponding codons described without alteringthe encoded polypeptide. Such nucleic acid variations are “silentvariations,” which are one species of conservatively modifiedvariations. Every nucleic acid sequence herein which encodes apolypeptide also describes every possible silent variation of thenucleic acid. One of skill will recognize that each codon in a nucleicacid (except AUG, which is ordinarily the only codon for methionine, andTGG, which is ordinarily the only codon for tryptophan) can be modifiedto yield a functionally identical molecule. Accordingly, each silentvariation of a nucleic acid which encodes a polypeptide is implicit ineach described sequence.

As to amino acid sequences, one of skill will recognize that individualsubstitutions, deletions or additions to a nucleic acid, peptide,polypeptide, or protein sequence which alters, adds or deletes a singleamino acid or a small percentage of amino acids in the encoded sequenceis a “conservatively modified variant” where the alteration results inthe substitution of an amino acid with a chemically similar amino acid.Conservative substitution tables providing functionally similar aminoacids are well known in the art. Such conservatively modified variantsare in addition to and do not exclude polymorphic variants, interspecieshomologs, and alleles of the disclosure.

The following eight groups each contain amino acids that areconservative substitutions for one another:

-   1) Alanine (A), Glycine (G);-   2) Aspartic acid (D), Glutamic acid (E);-   3) Asparagine (N), Glutamine (Q);

4) Arginine (R), Lysine (K);

-   5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);-   6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);-   7) Serine (S), Threonine (T); and-   8) Cysteine (C), Methionine (M)-   (see, e.g., Creighton, Proteins (1984)).

“Percentage of sequence identity” is determined by comparing twooptimally aligned sequences over a comparison window, wherein theportion of the polynucleotide or polypeptide sequence in the comparisonwindow may comprise additions or deletions (i.e., gaps) as compared tothe reference sequence (which does not comprise additions or deletions)for optimal alignment of the two sequences. The percentage is calculatedby determining the number of positions at which the identical nucleicacid base or amino acid residue occurs in both sequences to yield thenumber of matched positions, dividing the number of matched positions bythe total number of positions in the window of comparison andmultiplying the result by 100 to yield the percentage of sequenceidentity.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same or have a specifiedpercentage of amino acid residues or nucleotides that are the same(i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over aspecified region, when compared and aligned for maximum correspondenceover a comparison window or designated region) as measured using a BLASTor BLAST 2.0 sequence comparison algorithms with default parametersdescribed below, or by manual alignment and visual inspection (see,e.g., NCBI web site http://www.ncbi.nlm.nih.gov/BLAST/ or the like).Such sequences are then said to be “substantially identical.” Thisdefinition also refers to, or may be applied to, the compliment of atest sequence. The definition also includes sequences that havedeletions and/or additions, as well as those that have substitutions. Asdescribed below, the preferred algorithms can account for gaps and thelike. Preferably, identity exists over a region that is at least about25 amino acids or nucleotides in length, or more preferably over aregion that is 50-100 amino acids or nucleotides in length.

An amino acid or nucleotide base “position” is denoted by a number thatsequentially identifies each amino acid (or nucleotide base) in thereference sequence based on its position relative to the N-terminus (or5′-end). Due to deletions, insertions, truncations, fusions, and thelike that must be taken into account when determining an optimalalignment, in general the amino acid residue number in a test sequencedetermined by simply counting from the N-terminus will not necessarilybe the same as the number of its corresponding position in the referencesequence. For example, in a case where a variant has a deletion relativeto an aligned reference sequence, there will be no amino acid in thevariant that corresponds to a position in the reference sequence at thesite of deletion. Where there is an insertion in an aligned referencesequence, that insertion will not correspond to a numbered amino acidposition in the reference sequence. In the case of truncations orfusions there can be stretches of amino acids in either the reference oraligned sequence that do not correspond to any amino acid in thecorresponding sequence.

The terms “numbered with reference to” or “corresponding to,” when usedin the context of the numbering of a given amino acid or polynucleotidesequence, refers to the numbering of the residues of a specifiedreference sequence when the given amino acid or polynucleotide sequenceis compared to the reference sequence.

The term “amino acid side chain” refers to the functional substituentcontained on amino acids. For example, an amino acid side chain may bethe side chain of a naturally occurring amino acid. Naturally occurringamino acids are those encoded by the genetic code (e.g., alanine,arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, orvaline), as well as those amino acids that are later modified, e.g.,hydroxyproline, y-carboxyglutamate, and 0-phosphoserine. In embodiments,the amino acid side chain may be a non-natural amino acid side chain. Inembodiments, the amino acid side chain is H,

The term “non-natural amino acid side chain” refers to the functionalsubstituent of compounds that have the same basic chemical structure asa naturally occurring amino acid, i.e., an a carbon that is bound to ahydrogen, a carboxyl group, an amino group, and an R group, e.g.,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, allylalanine, 2-aminoisobutryric acid. Non-natural aminoacids are non-proteinogenic amino acids that either occur naturally orare chemically synthesized. Such analogs have modified R groups (e.g.,norleucine) or modified peptide backbones, but retain the same basicchemical structure as a naturally occurring amino acid. Non-limitingexamples include exo-cis-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxylicacid hydrochloride, cis-2-Aminocycloheptanecarboxylic acidhydrochloride, cis-6-Amino-3-cyclohexene-l-carboxylic acidhydrochloride, cis-2-Amino-2-methylcyclohexanecarboxylic acidhydrochloride, cis-2-Amino-2-methylcyclopentanecarboxylic acidhydrochloride ,2-(Boc-aminomethyl)benzoic acid, 2-(Boc-amino)octanedioicacid, Boc-4,5-dehydro-Leu-OH (dicyclohexylammonium),Boc-4-(Fmoc-amino)-L-phenylalanine, Boc-P-Homopyr-OH,Boc-(2-indanyl)-Gly-OH , 4-Boc-3-morpholineacetic acid,4-Boc-3-morpholineacetic acid , Boc-pentafluoro-D-phenylalanine,Boc-pentafluoro-L-phenylalanine, Boc-Phe(2-Br)-OH, Boc-Phe(4-Br)—OH,Boc-D-Phe(4-Br)—OH, Boc-D-Phe(3-Cl)—OH, Boc-Phe(4-NH2)—OH,Boc-Phe(3-NO2)—OH, Boc-Phe(3,5-F2)-0H,2-(4-Boc-piperazino)-2-(3,4-dimethoxyphenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(2-fluorophenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(3-fluorophenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(4-fluorophenyl)acetic acid purum,2-(4-Boc-piperazino)-2-(4-methoxyphenyl)acetic acid purum,2-(4-Boc-piperazino)-2-phenylacetic acid purum,2-(4-Boc-piperazino)-2-(3-pyridyl)acetic acid purum,2-(4-Boc-piperazino)-2-[4-(trifluoromethyl)phenyl]acetic acid purum,Bocβ-(2-quinolyl)-Ala-OH, N-Boc-1,2,3,6-tetrahydro-2-pyridinecarboxylicacid, Bocβ-(4-thiazolyl)-Ala-OH, Boc-β-(2-thienyl)-D-Ala-OH,Fmoc-N-(4-Boc-aminobutyl)-Gly-OH, Fmoc-N-(2-Boc-aminoethyl)-Gly-OH,Fmoc-N-(2,4-dimethoxybenzyl)-Gly-OH, Fmoc-(2-indanyl)-Gly-OH,Fmoc-pentafluoro-L-phenylalanine, Fmoc-Pen(Trt)-OH, Fmoc-Phe(2-Br)—OH,Fmoc-Phe(4-Br)—OH, Fmoc-Phe(3,5-F2)-OH, Fmoc-β-(4-thiazolyl)-Ala-OH,Fmoc-β-(2-thienyl)-Ala-OH, 4-(Hydroxymethyl)-D-phenylalanine.

“Nucleic acid” refers to nucleotides (e.g., deoxyribonucleotides orribonucleotides) and polymers thereof in either single-, double- ormultiple-stranded form, or complements thereof. The terms“polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in theusual and customary sense, to a linear sequence of nucleotides. The term“nucleotide” refers, in the usual and customary sense, to a single unitof a polynucleotide, i.e., a monomer. Nucleotides can beribonucleotides, deoxyribonucleotides, or modified versions thereof.Examples of polynucleotides contemplated herein include single anddouble stranded DNA, single and double stranded RNA, and hybridmolecules having mixtures of single and double stranded DNA and RNA.Examples of nucleic acid, e.g. polynucleotides contemplated hereininclude any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and anytypes of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and anyfragments thereof. The term “duplex” in the context of polynucleotidesrefers, in the usual and customary sense, to double strandedness.Nucleic acids can be linear or branched. For example, nucleic acids canbe a linear chain of nucleotides or the nucleic acids can be branched,e.g., such that the nucleic acids comprise one or more arms or branchesof nucleotides. Optionally, the branched nucleic acids are repetitivelybranched to form higher ordered structures such as dendrimers and thelike.

Nucleic acids, including e.g., nucleic acids with a phosphothioatebackbone, can include one or more reactive moieties. As used herein, theterm reactive moiety includes any group capable of reacting with anothermolecule, e.g., a nucleic acid or polypeptide through covalent,non-covalent or other interactions. By way of example, the nucleic acidcan include an amino acid reactive moiety that reacts with an amio acidon a protein or polypeptide through a covalent, non-covalent or otherinteraction.

The terms also encompass nucleic acids containing known nucleotideanalogs or modified backbone residues or linkages, which are synthetic,naturally occurring, and non-naturally occurring, which have similarbinding properties as the reference nucleic acid, and which aremetabolized in a manner similar to the reference nucleotides. Examplesof such analogs include, include, without limitation, phosphodiesterderivatives including, e.g., phosphoramidate, phosphorodiamidate,phosphorothioate (also known as phosphothioate having double bondedsulfur replacing oxygen in the phosphate), phosphorodithioate,phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate, orO-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES ANDANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well asmodifications to the nucleotide bases such as in 5-methyl cytidine orpseudouridine.; and peptide nucleic acid backbones and linkages. Otheranalog nucleic acids include those with positive backbones; non-ionicbackbones, modified sugars, and non-ribose backbones (e.g.phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) asknown in the art), including those described in U.S. Pat. Nos. 5,235,033and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580,CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds.Nucleic acids containing one or more carbocyclic sugars are alsoincluded within one definition of nucleic acids. Modifications of theribose-phosphate backbone may be done for a variety of reasons, e.g., toincrease the stability and half-life of such molecules in physiologicalenvironments or as probes on a biochip. Mixtures of naturally occurringnucleic acids and analogs can be made; alternatively, mixtures ofdifferent nucleic acid analogs, and mixtures of naturally occurringnucleic acids and analogs may be made. In embodiments, theinternucleotide linkages in DNA are phosphodiester, phosphodiesterderivatives, or a combination of both.

Nucleic acids can include nonspecific sequences. As used herein, theterm “nonspecific sequence” refers to a nucleic acid sequence thatcontains a series of residues that are not designed to be complementaryto or are only partially complementary to any other nucleic acidsequence. By way of example, a nonspecific nucleic acid sequence is asequence of nucleic acid residues that does not function as aninhibitory nucleic acid when contacted with a cell or organism.

An “antisense nucleic acid” as referred to herein is a nucleic acid(e.g., DNA or RNA molecule) that is complementary to at least a portionof a specific target nucleic acid (e.g., α2 or (β1 or both) and iscapable of reducing transcription of the target nucleic acid (e.g. mRNAfrom DNA), reducing the translation of the target nucleic acid (e.g.mRNA), altering transcript splicing (e.g. single stranded morpholinooligo), or interfering with the endogenous activity of the targetnucleic acid. See, e.g., Weintraub, Scientific American, 262:40 (1990).Typically, synthetic antisense nucleic acids (e.g. oligonucleotides) aregenerally between 15 and 25 bases in length. Thus, antisense nucleicacids are capable of hybridizing to (e.g. selectively hybridizing to) atarget nucleic acid (e.g., α2 or β31 or both). In embodiments, theantisense nucleic acid hybridizes to the target nucleic acid (e.g.α2 orβ1 or both) in vitro. In embodiments, the antisense nucleic acidhybridizes to the target nucleic acid (e.g. α2 or β1 or both) in a cell.In embodiments, the antisense nucleic acid hybridizes to the targetnucleic acid (e.g. α2 or β1 or both) in an organism. In embodiments, theantisense nucleic acid hybridizes to the target nucleic acid (e.g. α2 orβ1 or both) under physiological conditions. Antisense nucleic acids maycomprise naturally occurring nucleotides or modified nucleotides suchas, e.g., phosphorothioate, methylphosphonate, and -anomericsugar-phosphate, backbonemodified nucleotides.

In the cell, the antisense nucleic acids hybridize to the correspondingRNA (e.g., α2 RNA or β1 RNA or both) forming a double-stranded molecule.The antisense nucleic acids interfere with the endogenous behavior ofthe RNA (e.g., α2 RNA or β1 RNA or both) and inhibit its functionrelative to the absence of the antisense nucleic acid. Furthermore, thedouble-stranded molecule may be degraded via the RNAi pathway. The useof antisense methods to inhibit the in vitro translation of genes iswell known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)).Further, antisense molecules which bind directly to the DNA may be used.Antisense nucleic acids may be single or double stranded nucleic acids.Non-limiting examples of antisense nucleic acids include siRNAs(including their derivatives or pre-cursors, such as nucleotideanalogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (smallactivating RNAs) and small nucleolar RNAs (snoRNA) or certain of theirderivatives or pre-cursors.

The term “complement,” as used herein, refers to a nucleotide (e.g., RNAor DNA) or a sequence of nucleotides capable of base pairing with acomplementary nucleotide or sequence of nucleotides. As described hereinand commonly known in the art the complementary (matching) nucleotide ofadenosine is thymidine and the complementary (matching) nucleotide ofguanidine is cytosine. Thus, a complement may include a sequence ofnucleotides that base pair with corresponding complementary nucleotidesof a second nucleic acid sequence. The nucleotides of a complement maypartially or completely match the nucleotides of the second nucleic acidsequence. Where the nucleotides of the complement completely match eachnucleotide of the second nucleic acid sequence, the complement formsbase pairs with each nucleotide of the second nucleic acid sequence.Where the nucleotides of the complement partially match the nucleotidesof the second nucleic acid sequence only some of the nucleotides of thecomplement form base pairs with nucleotides of the second nucleic acidsequence. Examples of complementary sequences include coding and anon-coding sequences, wherein the non-coding sequence containscomplementary nucleotides to the coding sequence and thus forms thecomplement of the coding sequence. A further example of complementarysequences are sense and antisense sequences, wherein the sense sequencecontains complementary nucleotides to the antisense sequence and thusforms the complement of the antisense sequence.

As described herein the complementarity of sequences may be partial, inwhich only some of the nucleic acids match according to base pairing, orcomplete, where all the nucleic acids match according to base pairing.Thus, two sequences that are complementary to each other, may have aspecified percentage of nucleotides that are the same (i.e., about 60%identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).

II. Compounds

In an aspect is provided a compound, or a pharmaceutically acceptablethereof, having the formula:

R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

L¹ is a bond or —C(O)—.

R² is hydrogen or substituted or unsubstituted alkyl.

R³ is hydrogen, halogen, —CX³ _(3,) —CHX³ _(2,) —CH₂X³, —OCX³ ₃,—OCH₂X³, —OCHX³ ₂, —CN, —SO_(n3)R^(3D), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3C),—C(O)OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D), —NR^(3A)SO₂R^(3D),—NR^(3A)C(O)R^(3C), —NR^(3A)C(O)O R^(3C), —NR^(3A)OR^(3C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl.

R⁴ is hydrogen or substituted or unsubstituted alkyl.

W¹ is 0, S, or NR⁸.

W² is 0, S, or NR⁵.

R⁵ is hydrogen or substituted or unsubstituted alkyl.

L² is a bond or —C(R⁶)₂—.

R⁶ is hydrogen, ═NH, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl. It will be understood that when R⁶ is ═NH,then L² is —C(═NH)—, in order to satisfy the proper valency requirementsfor all atoms and could also be described as two R⁶ groups combining toform a single ═NH. For the purposes of optionally joining W¹ and R⁶, itwill be understood that when R⁶ is ═NH, W¹ and R⁶ may be joined to forma 5 to 6 membered heterocycloalkyl, or substituted or unsubstituted 5 to6 membered heteroaryl, which includes the ═N— in place of R⁶ resulting 5to 6 membered heterocycloalkyl, or substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, L² is C(═R⁶)— when R⁶ is ═NH.

W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

R⁷ is hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷,—OCHX⁷ ₂, —CN, —SO_(n7)R^(7D), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B) —N(O)m₇, —NR^(7A)R^(7B), —C(O)R^(7C),—C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)O R^(7C), —NR^(7A)OR^(7C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl.

R⁸ is hydrogen or substituted or unsubstituted alkyl.

R^(3A), R_(3B), R^(3C), R^(3D), R^(7A), R^(7B), R^(7C), and R^(7D) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, orC₁-C₄ alkyl), substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl)

R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

R^(7A) and R^(7B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

Each X, X³, and X⁷ are independently —F, —Cl, −Br, or —I.

n3 and n7 are independently an integer from 0 to 4.

m3, m7, v3 and v7 are independently 1 or 2.

In embodiments, the compound has the formula:

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

R²¹ is independently halogen, —CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹, —OCX²¹ ₃,—OCH₂X²¹, —OCHX²¹ _(2,) —CN, —SO_(v21)R^(21D), —SO_(v21)NR^(21A)R^(21B),—NHC(O)NR^(21A)R^(21B), —N(O)_(m21), —N R^(21A)R^(21B), —C(O)R^(21C),—C(O)—OR^(21C), —C(O)NR^(21A)R^(21B), —OR^(21D), —NR^(21A)SO₂R^(21D),—NR^(21A)C(O)R^(21C), —NR^(21A)C(O)OR^(21C), —NR^(21A)OR^(21C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl.

Two adjacent R²¹ substituents may optionally be joined to form asubstituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, two adjacent R²¹ substituents are joined toform an R²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, two adjacent R²¹ substituents are joined toform an R²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, twoadjacent R²¹ substituents are joined to form an R²²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).In embodiments, two adjacent R²² substituents are joined to form anR²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, two adjacent R²¹ substituents are joined toform an R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

z21 is an integer from 0 to 5.

R^(21A), R^(21B), R^(21C), and R^(21D) are independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R^(21A) and R^(21B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).e

Each X²¹ is independently —F, —Cl, —Br, or —I.

n21 is independently an integer from 0 to 4.

m21 and v21 are independently 1 or 2.

In embodiments, R¹ is unsubstituted C₁-C₆ alkyl.

In embodiments, R¹ is

or substituted or unsubstituted C₄-C₈ alkyl.

R¹⁰ is independently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰, —OCX¹⁰ ₃,—OCH₂X¹⁰ , —OCHX^(10C) ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10),—NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R_(10B),—OR^(10D), —NR^(10A)SO₂R_(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

Two adjacent R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R^(10A), R^(10B), R^(10C), and R^(10D) are independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R^(10A) and R^(10B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

X¹⁰ is independently —F, —Cl, —Br, or —I.

n10 is independently an integer from 0 to 4.

m10 and v10 are independently 1 or 2.

z10 is an integer from 0 to 5.

In embodiments, R¹ is substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted

heteroaryl. In embodiments, R¹ is or substituted or unsubstituted C₄-C₈alkyl.

R⁹ is independently halogen, —CX⁹ ₃, 13 CHX⁹ ₂, —CH₂X⁹, —OCX⁹ ₃,—OCH₂X⁹, —OCHX⁹ ₂, —CN, —SO_(n9)R^(9D), —SO_(v9)NR^(9A)R^(9B),—NHC(O)NR^(9A)R^(9B), —N(O)_(m9), —NR^(9A)R^(9B), —C(O)R^(9C),—C(O)—OR^(9C), —C(O)NR^(9A)R^(9B), —OR^(9D), —NR^(9A)SO₂R^(9D),—NR^(9A)C(O)R^(9C)-—NR^(9A)C(O)O R^(9C), —NR^(9A)OR^(9C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or a detectable moiety; two adjacent R⁹substituents may optionally be joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

Each R^(9A), R^(9B), R^(9C), R^(9D) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R^(9A) and R^(9B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

Each X⁹ is independently —F, —Cl, —Br, or —I.

n9 is independently an integer from 0 to 4.

m9 and v9 are independently 1 or 2.

z9 is an integer from 0 to 5.

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹⁰ is

or substituted or unsubstituted C₄-C₈ alkyl. In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is substituted or unsubstituted C₄-C₈ alkyl. Inembodiments, It R¹ is unsubstituted C₄-C₈ alkyl. In embodiments, R¹ isunsubstituted C₅ alkyl.

In embodiments, R¹ is

In embodiments, R¹ is

wherein R¹⁰ is independently substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl,

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

embodiments R¹ is

In embodiments, R¹ is substituted or unsubstituted cycloalkyl. Inembodiments, R¹ is substituted cycloalkyl. In embodiments, R¹ isunsubstituted cycloalkyl. In embodiments, R¹ is substituted orunsubstituted cyclohexyl. In embodiments, R¹ is substituted cyclohexyl.In embodiments, R¹ is methyl substituted cyclohexyl. In embodiments, R¹is unsubstituted cyclohexyl. In embodiments, R¹ is substituted orunsubstituted adamantyl. In embodiments, R¹ is substituted adamantyl. Inembodiments, R¹ is unsubstituted adamantyl.

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

R^(10.1), R^(10.2), R^(10.3), R^(10.4), and R^(10.5) are independentlyhydrogen or a value of R¹⁰ as described herein, including in anembodiment.

In embodiments, R³ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. Inembodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R³ is hydrogen. In embodiments, R³ is hydrogen orsubstituted or unsubstituted alkyl. In embodiments, R³ is a moiety thatwhen combined with the attached —OC(O)— of the compounds describedherein forms a prodrug moiety (e.g., moiety —C(O)OR³ is a substrate foran esterase or amidase (e.g., in an organism) that may be catalyzed bythe enzyme to form C(O)OH).

In embodiments, L² is C(R⁶)₂—.

In embodiments, L² is a bond or —CHR⁶—. In embodiments, L² is —CHR⁶—. Inembodiments, L² is a bond. In embodiments, L² is —C(CH₃)₂—. Inembodiments, L² is —C(═NH)—.

In embodiments, R⁶ is unsubstituted alkyl. In embodiments, R⁶ ishydrogen. In embodiments, R⁶ is oxo-substituted alkyl. In embodiments,R⁶ is═NH.

In embodiments, R⁷ is unsubstituted C₁-C₆ alkyl. In embodiments, R⁷ isunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, W² is NH. In embodiments, W² is S. In embodiments, W² isO. In embodiments, W² is NR⁵. In embodiments, R⁵ is hydrogen.

In embodiments, W¹ is O. In embodiments, W¹ is S. In embodiments, W¹ isNH. In embodiments, W¹ is NR⁸. In embodiments, R⁸ is hydrogen.

In embodiments, W¹ and R⁶ are joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl or substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, W¹ and R⁶ are joined to form a substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments, W¹ and R⁶ are joined to form

In embodiments,

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer form 0 to 4; C)

D)

wherein R⁷ is subsititued or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; F)

wherein z21 is an integer from 0 to 2; or G)

wherein z21 is an integer from 1 to 5.In embodiments,

wherein z21 is an integer from 0 to 5.In embodiments,

wherein z21 is an integer from 0 to 4. In embodiments,

In embodiments,

wherein R⁷ is substituted or unsubstituted cycloalkyl. In embodiments,

wherein z21 is an integer from 0 to 3. In embodiments,

wherein z21 is an integer from 0 to 2. In embodiments,

wherein z21 is an integer from 1 to 5.

In embodiments,

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer from 0 to 4; C)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; or F)

wherein z21 is an integer from 0 to 2.In embodiments,

wherein z21 is an integer from 0 to 5. In embodiments,

wherein z21 is an integer from 0 to 4. In embodiments,

In embodiments,

wherein R⁷ is substituted or unsubstituted cycloalkyl. In embodiments,

wherein z21 is an integer from 0 to 3. In embodiments,

wherein z21 is an integer from 0 to 2.

In embodiments,

In embodiments,

In embodiments, R², R³, R⁴, and R⁵ are hydrogen. In embodiments, R², R⁴,R⁵, and R⁸ are hydrogen.

In embodiments, L¹ is a bond. In embodiments, L¹ is —C(O)—.

In embodiments, Ring A is phenyl.

In embodiments, z21 is an integer from 1 to 5. In embodiments, z21 is 0.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

R¹ is

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer from 0 to 4; C)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; F)

wherein z21 is an integer from 0 to 2; G)

wherein z21 is an integer from 1 to 5; or H)

wherein z21 is an integer from 1 to 5.

In embodiments, the compound has the formula:

R^(l) is

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer for 0 to 4; C)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; F)

wherein z21 is an integer from 0 to 2; or G)

wherein z21 is an integer from 1 to 5.

In embodiments, the compound has the formula:

R¹ is

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer from 0 to 4; C)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; or F)

wherein z21 is an integer from 0 to 2; or G)

wherein z21 is an integer from 1 to 5.

In embodiments, the compound has the formula: R¹ is

R¹ is

is A)

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer from 0 to 4; C) , D)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; or F)

wherein z21 is an integer from 0 to 2.

In embodiments, R¹ is independently substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹ is independently substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2 to 8 memberedheteroalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(i) isindependently substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R¹ is R¹¹-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₄-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹¹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R¹¹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R¹¹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹¹-substitutedaryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R¹¹-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is R¹¹-substituted alkyl (e.g. C₁-C₈ alkyl, C₄-C₈alkyl, C₆-C₁₀ alkyl, or C₁-C₄ alkyl), R¹¹-substituted heteroalkyl (e.g.2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹¹-substituted cycloalkyl (e.g. C₃-Ca cycloalkyl, C₄-C₈cycloalkyl, or C₅-C₆ cycloalkyl), R¹¹-substituted heterocycloalkyl (e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), R¹¹-substituted aryl (e.g. C₆-C₁₀ arylor C₆ aryl), or R¹¹-substituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R₁ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is R¹¹-substituted alkyl (e.g. C₁-C₈ alkyl, C₄-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹ isR¹¹-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹ isR¹¹-substituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl). In embodiments, R¹ is R¹¹-substitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,IV is R¹¹-substituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl). Inembodiments, R¹ is R¹¹-substituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R¹ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R^(i) is unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl). In embodiments, R¹ is unsubstitutedcycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R¹ is unsubstituted heterocycloalkyl (e.g.3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R¹ is unsubstitutedaryl (e.g. C₆-C₁₀ aryl or C₆ aryl). In embodiments, R¹ is unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹ is R¹¹-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R¹ is substituted or unsubstitutedpyridyl. In embodiments, R¹ is R¹¹-substituted pyridyl. In embodiments,R¹ is unsubstituted pyridyl. In embodiments, R¹ is substituted orunsubstituted pyrimidinyl. In embodiments, R¹ is R¹¹-substitutedpyrimidinyl. In embodiments, R¹ is unsubstituted pyrimidinyl. Inembodiments, R¹ is substituted or unsubstituted phenyl. In embodiments,R¹ is R¹¹-substituted phenyl. In embodiments, R¹ is unsubstitutedphenyl.

R¹¹ is independently halogen, —CX¹¹ ₃, —CHX¹¹ ₂, —CH₂X¹¹, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H,

—NHC═(O)H, —NHC(O)OH, —NHOH, —OCX¹¹ ₃, —OCHX¹¹ ₂, —OCH₂X¹¹,R¹²-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R¹²-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-Ca cycloalkyl, or C₅-C₆ cycloalkyl), R¹²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR¹²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹¹ is —F, —Cl, —Br, or —I. In embodiments, R¹¹ is independently —F. Inembodiments, R¹¹ is independently —Cl. In embodiments, R¹¹ isindependently —Br. In embodiments, R¹¹ is independently —I.

It¹² is independently halogen, —CX¹² ₃, —CHX¹² ₂, —CH₂X¹², —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —HNC═(O)H, —NHC(O)OH, —NHOH, —OCX¹²₃, —OCHX¹² ₂, —OCH₂X¹², R¹³-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R^(H)-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R¹³-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R¹³-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹³-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R¹³-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹² is —F, —Cl,—Br, or —I.

R¹³ is independently halogen, —CX¹³ ₃, —CHX¹³ ₂, —CH₂X¹³, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX¹³₃, —OCHX¹³ ₂, —OCH₂X¹³, unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹³ is —F, —Cl,—Br, or —I.

In embodiments, R² is substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R² is substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R² is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl).

In embodiments, R² is R¹⁴-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R² isR¹⁴-substituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R² is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R² is hydrogen. In embodiments,R² is unsubstituted methyl. In embodiments, R² is unsubstituted ethyl.In embodiments, R² is unsubstituted propyl.

R¹⁴ is independently halogen, —CX¹⁴ ₃, —CHX¹⁴ ₂, —CH₂X¹⁴, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH_(2,) —ONH₂,—NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX¹⁴,—OCHX¹⁴ ₂, —OCH₂X¹⁴, unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹⁴ is —F, —Cl,—Br, or —I.

In embodiments, R³ is independently hydrogen, halogen, —CF₃, —CBr₃,—CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂C₁, —CH₂I,—OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂, —OCHCl₂, —OCHI₂, —OCH₂F,—OC H₂Br, —OCH₂C₁, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³ is independently hydrogen, halogen, —CF₃, —CBr₃,—CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂, —OCHCl₂, —OCHI₂, —OCH₂F,—OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R¹⁵-substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), 1V-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁵-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R³ is independently hydrogen, halogen, —CF₃, —CBr₃,—CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂, —OCHCl₂, —OCHI₂, —OCH₂F,—OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, R³ is independently hydrogen.

In embodiments, R³ is R¹⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R³ isR¹⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R³ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R³ is R¹⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments,R³ is R¹⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R³ is an unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R³ is R¹⁵-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R³ is R¹⁵-substituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃ -C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R³ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R³ isR¹⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R³ is R¹⁵-13 substitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R³ is an unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R³ is R¹⁵-substituted orunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R³ is R¹⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R³ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R³ is R¹⁵-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³is R¹⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³ is R¹⁵-substituted or unsubstituted C₁-C₈ alkyl. Inembodiments, R³ is R¹⁵-substituted or unsubstituted C₃-C₈ alkyl. Inembodiments, R³ is R¹⁵-substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R³ is R¹⁵-substituted C₁ alkyl. In embodiments, R³ isR¹⁵-substituted C₂ alkyl. In embodiments, R³ is I0⁵-substituted C₃alkyl.

In embodiments, R³ is R¹⁵-substituted C₄ alkyl. In embodiments, R³ isIC-substituted C₅ alkyl. In embodiments, R³ is I0⁵-substituted C₆ alkyl.In embodiments, R³ is R¹⁵-substituted C₇ alkyl. In embodiments, R³ isR¹⁵-substituted C₈ alkyl. In embodiments, R³ is unsubstituted C₁ alkyl.In embodiments, R³ is unsubstituted C₂ alkyl. In embodiments, R³ isunsubstituted C₃ alkyl. In embodiments, R³ is unsubstituted C₄ alkyl. Inembodiments, R³ is unsubstituted C₅ alkyl. In embodiments, R³ isunsubstituted C₆ alkyl. In embodiments, R³ is unsubstituted C₇ alkyl. Inembodiments, R³ is unsubstituted C₈ alkyl. In embodiments, R³ isR¹⁵-substituted or unsubstituted linear C₁-C₈ alkyl. In embodiments, R³is R¹⁵-substituted or unsubstituted linear C₃-C₈ alkyl. In embodiments,R³ is R¹⁵-substituted or unsubstituted linear C₁-C₆ alkyl. Inembodiments, R³ is R¹⁵-substituted linear C₁ alkyl. In embodiments,

R³ is R¹⁵-substituted linear C₂ alkyl. In embodiments, R³ isR¹⁵-substituted linear C₃ alkyl. In embodiments, R³ is R¹⁵-substitutedlinear C₄ alkyl. In embodiments, R³ is R¹⁵-substituted linear C₅ alkyl.In embodiments, R³ is R¹⁵-substituted linear C₆ alkyl. In embodiments,R³ is R¹⁵-substituted linear C₇ alkyl. In embodiments, R³ isR¹⁵-substituted linear C₈ alkyl. In embodiments, R³ is substitutedlinear C₁-C₈ alkyl. In embodiments, R³ is substituted linear

C₃-C₈ alkyl. In embodiments, R³ is substituted linear C₁-C₆ alkyl. Inembodiments, R³ is unsubstituted linear C₁-C₈ alkyl. In embodiments, R³is unsubstituted linear C₃-C₈ alkyl. In embodiments, R³ is unsubstitutedlinear C₁-C₆ alkyl. In embodiments, R³ is substituted linear C₁ alkyl.In embodiments, R³ is substituted linear C₂ alkyl. In embodiments, R³ issubstituted linear C₃ alkyl. In embodiments, R³ is substituted linear C₄alkyl. In embodiments, R³ is substituted linear C₅ alkyl. Inembodiments, R³ is substituted linear C₆ alkyl. In embodiments, R³ issubstituted linear C₇ alkyl. In embodiments, R³ is substituted linear C₈alkyl. In embodiments, R³ is unsubstituted linear C₁ alkyl. Inembodiments, R³ is unsubstituted linear C₂ alkyl. In embodiments, R³ isunsubstituted linear C₃ alkyl. In embodiments, R³ is unsubstitutedlinear C₄ alkyl. In embodiments, R³ is unsubstituted linear C₅ alkyl. Inembodiments, R³ is unsubstituted linear C₆ alkyl. In embodiments, R³ isunsubstituted linear C₇ alkyl. In embodiments, R³ is unsubstitutedlinear C₈ alkyl. In embodiments, R³ is R¹⁵-substituted or unsubstitutedbranched C₃-C₈ alkyl. In embodiments, R³ is R¹⁵-substituted branched C₃alkyl. In embodiments, R³ is R¹⁵-substituted branched C₄ alkyl. Inembodiments, R³ is I0⁵-substituted branched Cs alkyl. In embodiments, R³is R¹⁵-substituted branched C₆ alkyl. In embodiments, R³ isR¹⁵-substituted branched C₇ alkyl. In embodiments, R³ is R¹⁵-substitutedbranched C₈ alkyl. In embodiments, R³ is substituted branched C₃-C₈alkyl. In embodiments, R³ is unsubstituted branched C₃-C₈ alkyl. Inembodiments, R³ is substituted branched C₃ alkyl. In embodiments, R³ issubstituted branched C₄ alkyl. In embodiments, R³ is substitutedbranched C₅ alkyl. In embodiments, R³ is substituted branched C₆ alkyl.In embodiments, R³ is substituted branched C₇ alkyl. In embodiments, R³is substituted branched C₈ alkyl. In embodiments, R³ is unsubstitutedbranched C₃ alkyl. In embodiments, R³ is unsubstituted branched C₄alkyl. In embodiments,

R³ is unsubstituted branched Cs alkyl. In embodiments, R³ isunsubstituted branched C₆ alkyl. In embodiments, R³ is unsubstitutedbranched C₇ alkyl. In embodiments, R³ is unsubstituted branched C₈alkyl.

In embodiments, R³ is R¹⁵-substituted or unsubstituted C4-C₇ cycloalkyl.In embodiments, R³ is R¹⁵-substituted C₄ cycloalkyl. In embodiments, R³is R¹⁵-substituted C₅ cycloalkyl. In embodiments, R³ is R¹⁵-substitutedC₆ cycloalkyl. In embodiments, R³ is R¹⁵-substituted C₇ cycloalkyl. Inembodiments, R³ is unsubstituted C₄ cycloalkyl. In embodiments, R³ isunsubstituted C₅ cycloalkyl. In embodiments, R³ is unsubstituted C₆cycloalkyl. In embodiments, R³ is unsubstituted C₇ cycloalkyl.

In embodiments, R³ is unsubstituted methyl. In embodiments, R³ isunsubstituted ethyl. In embodiments, R³ is unsubstituted propyl. Inembodiments, R³ is unsubstituted butyl. In embodiments, R³ isunsubstituted tert-butyl. In embodiments, R³ is unsubstitutedcyclopropyl. In embodiments, R³ is unsubstituted cyclobutyl. Inembodiments, R³ is unsubstituted cyclopentyl. In embodiments, R³ isunsubstituted cyclohexyl.

In embodiments, R³ is (acyloxy)alkyl or [(alkoxycarbonyl)oxy]methyl. Inembodiments, R³ is (acyloxy)alkyl. In embodiments, R³ is[(alkoxycarbonyl)oxy]methyl. In embodiments, R³ is [(C₁-C₄alkoxycarbonyl)oxy]methyl. In embodiments, R³ is R¹⁵-substituted C₁-C₄alkyl and R¹⁵ is (acyloxy)alkyl. In embodiments, R³ is R¹⁵-substitutedC₁-C₄ alkyl and R¹⁵ is [(alkoxycarbonyl)oxy]methyl. In embodiments, R³is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵ is [(C₁-C₄alkoxycarbonyl)oxy]methyl.

In embodiments, R³ is (oxodioxolyl)methyl. In embodiments, R³ is

In embodiments, R³ is

In embodiments, R³ is

In embodiments, R³ is

In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵ isoxodioxolyl. In embodiments, R³ is 1V-substituted C₁-C₄ alkyl and R¹⁵ is

In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵ is

In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵ is

In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R^(15 is)

In embodiments, —R³ is

In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵ is substitutedmorpholinyl. In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵is R¹⁶-substituted morpholinyl. In embodiments, R³ is R¹⁵-substitutedC₁-C₄ alkyl and R¹⁵ is unsubstituted morpholinyl. In embodiments, R³ isR¹⁵-substituted C₁-C₄ alkyl and R¹⁵ is

In embodiments, R³ is R¹⁵-substituted C₁-C₄ alkyl and R¹⁵ is

In embodiments, R³ is R¹⁵-substituted C₆-C₁₂ aryl. In embodiments, R³ isR¹⁵-substituted phenyl. In embodiments, R³ is R¹⁵-substituted naphthyl.In embodiments, R³ is substituted C₆-C₁₂ aryl. In embodiments, R³ issubstituted phenyl. In embodiments, R³ is substituted naphthyl. Inembodiments, R³ is unsubstituted C₆-C₁₂ aryl. In embodiments, R³ isunsubstituted phenyl. In embodiments, R³ is unsubstituted naphthyl.

In embodiments, R³ is R¹⁵-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl. In embodiments, R³ is R¹⁵-substituted 4-memberedheterocycloalkyl. In embodiments, R³ is R¹⁵-substituted 5-memberedheterocycloalkyl. In embodiments, R³ is R¹⁵-substituted 6-memberedheterocycloalkyl. In embodiments, R³ is R¹⁵-substituted 7-memberedheterocycloalkyl. In embodiments, R³ is R¹⁵-substituted 8-memberedheterocycloalkyl. In embodiments, R³ is unsubstituted 4-memberedheterocycloalkyl. In embodiments, R³ is unsubstituted 5-memberedheterocycloalkyl. In embodiments, R³ is unsubstituted 6-memberedheterocycloalkyl. In embodiments, R³ is unsubstituted 7-memberedheterocycloalkyl. In embodiments, R³ is unsubstituted 8-memberedheterocycloalkyl.

R¹⁵ is independently oxo, halogen, —CC₁₃, —CBr₃, —CF₃, 13 CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄ H, —SO₂NH₂, NHNH₂, ONH₂,NHC(O)NHNH₂, NHC(O)NH₂, -NHSO2H, -NHC(O)H, -NHC(O)0H, -NHOH,-OCC13,-OCF₃, -OCBr3,-O CI3, —OCHCl₂, —OCHBr₂,—OCHI₂, —OCHF₂,-OCH2C1,-OCH₂Br, -OCH2I, —OCH₂F, -N₃, R¹⁶-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁶-substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R¹⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR¹⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R¹⁵ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃, —CHF₂, —CHBr₂, —CHCl₂, CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁵ is independently oxo. In embodiments, R¹⁵ isindependently halogen. In embodiments, R¹⁵ is independently —CCl₃. Inembodiments, R¹⁵ is independently —CBr₃. In embodiments, R¹⁵ isindependently —CF₃. In embodiments, R¹⁵ is independently —CI₃. Inembodiments, R¹⁵ is independently CHCl₂. In embodiments, R¹⁵ isindependently —CHBr₂. In embodiments, R¹⁵ is independently —CHF₂. Inembodiments, R¹⁵ is independently —CHI₂. In embodiments, R¹⁵ isindependently —CH₂Cl In embodiments, R¹⁵ is independently —CH₂Br. Inembodiments, R¹⁵ is independently —CH₂F. In embodiments, R¹⁵ isindependently —CH₂I. In embodiments, R¹⁵ is independently —CN. Inembodiments, R¹⁵ is independently —OH. In embodiments, R¹⁵ isindependently —NH₂. In embodiments, R¹⁵ is independently —COOH. Inembodiments, R¹⁵ is independently —CONH₂. In embodiments, R¹⁵ isindependently —NO_(2.) In embodiments, R¹⁵ is independently —SH. Inembodiments, R¹⁵ is independently —SO₃H. In embodiments, R¹⁵ isindependently —SO₄H. In embodiments, R¹⁵ is independently —SO₂NH₂. Inembodiments, R¹⁵ is independently NHNH₂. In embodiments, R¹⁵ isindependently ONH₂. In embodiments, R¹⁵ is independently NHC(O)NHNH₂. Inembodiments, R¹⁵ is independently NHC(O)NH₂. In embodiments, R¹⁵ isindependently —NHSO₂H. In embodiments, R¹⁵ is independently —NHC(O)H. Inembodiments, R¹⁵ is independently —NHC(O)OH. In embodiments, R¹⁵ isindependently —NHOH. In embodiments, R¹⁵ is independently —OCC₁₃. Inembodiments, R¹⁵ is independently —OCF₃. In embodiments, R¹⁵ isindependently —OCBr₃. In embodiments, R¹⁵ is independently —OCI₃. Inembodiments, R¹⁵ is independently —OCHCl₂. In embodiments, IV isindependently —OCHBr₂. In embodiments, R¹⁵ is independently —OCHI₂. Inembodiments, R¹⁵ is independently —OCHF₂. In embodiments, R¹⁵ isindependently —OCH₂Cl. In embodiments, R¹⁵ is independently —OCH₂Br. Inembodiments, R¹⁵ is independently —OCH₂I. In embodiments, R¹⁵ isindependently —OCH₂F. In embodiments, R¹⁵ is independently —N₃.

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁵ isR¹⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R¹⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R¹⁵ is R¹⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R¹⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁵ is R¹⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, IV is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R¹⁵ is R¹⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R¹⁵ is morpholinyl.

In embodiments, —R³is

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁵ isR¹⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R¹⁵ is R¹⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁵ is V-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R¹⁵ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

R¹⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —

CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCC13, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃,R¹⁷-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R¹⁷-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R¹⁷-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R¹⁷-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R¹⁷-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R¹⁷-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁶ isindependently oxo, halogen, —CF₃, —CBr₃, —CCl₃, -CI₃, —CHF₂, —CHBr₂,—CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃, —OCBr₃, —OCCl₃,—OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OC H₂Br, —OCH₂Cl,—OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁶ isindependently —OH. In embodiments, R¹⁶ is independently —OCH₃. Inembodiments, R¹⁶ is independently —OCH₂CH₃. In embodiments, R¹⁶ isindependently —F. In embodiments, R¹⁶ is independently —NHC(O)CH₃. Inembodiments, R¹⁶ is independently —COOH. In embodiments, R¹⁶ isindependently —SO₂NH_(2.)

In embodiments, R¹⁷ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃, —CHF₂, —CHBr₂, —CHC₁₂, —CHI₂, −CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂, —OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3A), R³B, R^(3c), and R^(3D) are independentlyhydrogen, halogen, —CF₃, —CBr₃, —CCl₃, —Cl₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂,—CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂,—OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, R¹⁵-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁵-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁵-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R¹⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom are joined to form an R¹⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orR¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom are joined to form an R¹⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl. In embodiments, R^(3A) and R^(3B)substituents bonded to the same nitrogen atom are joined to form anR¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(3C) is unsubstituted methyl. In embodiments, ^(R3C)is unsubstituted ethyl. In embodiments, R^(3C) is unsubstituted propyl.In embodiments, R^(3C) is unsubstituted butyl. In embodiments, R^(3C) isunsubstituted tert-butyl. In embodiments, R^(3C) is unsubstitutedcyclopropyl. In embodiments, R^(3C) is unsubstituted cyclobutyl. Inembodiments, R^(3C) is unsubstituted cyclopentyl. In embodiments, R^(3C)is unsubstituted cyclohexyl.

In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁴ is substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁴ is an unsubstituted alkyl (e.g. C₁-C₁ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl).

In embodiments, R⁴ is R¹⁸-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁴ isR¹¹-substituted alkyl (e.g. C₁-Cs alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁴ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁴ is hydrogen. In embodiments,R⁴ is unsubstituted methyl. In embodiments, R⁴ is unsubstituted ethyl.In embodiments, R⁴ is unsubstituted propyl.

R¹⁸ is independently halogen, —CX¹⁸ ₃, —CHX¹⁸ ₂, —CH₂X¹⁸, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX¹⁸₃, —OCHX¹⁸ ₃, —OCHX¹⁸ ₂, unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹⁸ is —F, —Cl,—Br, or —I.

In embodiments, R⁵ is substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁵ is substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁵ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl).

In embodiments, R⁵ is R¹⁹-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁵ is substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁵ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R⁵ is hydrogen. In embodiments, R⁵ isunsubstituted methyl. In embodiments, R⁵ is unsubstituted ethyl. Inembodiments, R⁵ is unsubstituted propyl.

It¹⁹ is independently halogen, —CX¹⁹ ₃, —CHX¹⁹ ₂, —CH₂X¹⁹, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, ——NHNH₂, ONH₂,NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX¹⁹₃, —OCHX¹⁹ ₂, —OCH₂X¹⁹, unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹⁹ is—F, —Cl, —Br,and —I.

In embodiments, R⁶ is substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ is substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁶ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl). In embodiments, R⁶ is substituted or unsubstituted heteroalkyl(e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁶ is substituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁶ is unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl).

In embodiments, R⁶ is R²⁰-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ isR²⁰-substituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁶ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁶ is R²⁰-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁶ isR²⁰-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁶ isunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁶ ishydrogen. In embodiments, R⁶ is unsubstituted methyl. In embodiments, R⁶is unsubstituted ethyl. In embodiments, R⁶ is unsubstituted propyl.

In embodiments, W¹ and R⁶ are joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl. In embodiments, W¹ and R⁶ are joined to form a substitutedor unsubstituted heterocycloalkyl. In embodiments, W¹ and R⁶ are joinedto form a substituted heterocycloalkyl. In embodiments, W¹ and R⁶ arejoined to form an unsubstituted heterocycloalkyl. In embodiments, W¹ andR⁶ are joined to form a substituted or unsubstituted heteroaryl. Inembodiments, W¹ and R⁶ are joined to form a substituted heteroaryl. Inembodiments, W¹ and R⁶ are joined to form an unsubstituted heteroaryl.In embodiments, W¹ and R⁶ are joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, W¹ and R⁶ arejoined to form a substituted or unsubstituted 5 to 6 memberedheterocycloalkyl. In embodiments, W¹ and R⁶ are joined to form asubstituted 5 to 6 membered heterocycloalkyl. In embodiments, W¹ and R⁶are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl. Inembodiments, W¹ and R⁶ are joined to form a substituted or unsubstituted5 to 6 membered heteroaryl. In embodiments, W¹ and R⁶ are joined to forma substituted 5 to 6 membered heteroaryl. In embodiments, W¹ and R⁶ arejoined to form an unsubstituted 5 to 6 membered heteroaryl.

In embodiments, W¹ and R⁶ are joined to form R²⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orV-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, W¹ and R⁶ are joined to form R²⁰-substitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orR²⁰-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, W¹and R⁶ are joined to form an unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or unsubstituted heteroaryl (e.g. 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, W¹ and R⁶ are joined to form R²⁰-substitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,W¹ and R⁶ are joined to form R²⁰-substituted heteroaryl (e.g. 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, ItAT' and R⁶ are joined to form anunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, W¹ and R⁶ are joined to form an unsubstituted heteroaryl(e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R²⁰ is independently oxo, halogen, —CX²⁰ ₃, —CHX²⁰ ₂, —CH₂X²⁰ , —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,ONH₂, NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—OCX²⁰ ₃, —OCHX²⁰ ₂, —OCH₂X²⁰, unsubstituted alkyl (e.g. C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl orC₆ aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X²⁰ is —F,—Cl, —Br, or —I.

In embodiments, R⁷ is independently hydrogen, oxo, halogen, —CF₃, —CBr₃,—CCl₃, —Cl₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F,—OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R⁷ is independently —F. In embodiments, R⁷is independently —Cl. In embodiments, R⁷ is independently —Br. Inembodiments, R⁷ is independently —I.

In embodiments, R⁷ is independently hydrogen, oxo, halogen, —CF₃, —CBr₃,—CCl₃, —CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F,—OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R²¹-substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²¹-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²¹-substituted or unsubstituted cycloalkyl (e.g., C₃-C⁸cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²¹-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²¹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R⁷ is independently hydrogen, oxo, halogen, —CF₃, CBr₃,—CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂, —OCHCl₂, —OCHI₂, —OCH₂F,—OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁷ is R²¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ isR²¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-Calkyl, or C₁-C₄ alkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments,R⁷ is R²¹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R⁷ is an unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁷ is R²¹-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁷ is R²¹-substituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁷ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁷ isR²¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁷ is R²¹-substitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R⁷ is an unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁷ is R²¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁷is R²¹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁷is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, IC is substituted or unsubstituted cyclohexyl,substituted or unsubstituted adamantyl, substituted or unsubstituted1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro5H-benzo[7]annulenyl,substituted or unsubstituted 2,3-dihydro-1H-indenyl, substituted orunsubstituted (2r,3as,5r,6as)-octahydro-2,5-methanopentyl, substitutedor unsubstituted bicyclo[3.1.1]heptanyl, substituted or unsubstitutedbicyclo[2.2.2]octanyl, substituted or unsubstituted spiro[2.5]octane,substituted or unsubstituted spiro[3.3]heptanyl, substituted orunsubstituted spiro[5.5]undecanyl, substituted or unsubstituted(1r,3r,5r,7r)-spiro[adamantane-2,1′-cyclohexanyl], substituted orunsubstituted (1R,3r,8S)-tricyclo[4.3.1.13,8]undecanyl, or substitutedor unsubstituted bicyclo[2.2.1]heptan-2-yl.

In embodiments, IC is R¹¹-substituted or unsubstituted cyclohexyl,R²¹-substituted or unsubstituted adamantyl, R²¹-substituted orunsubstituted 1,2,3,4-tetrahydronaphthalenyl, R²¹-substituted orunsubstituted 2,3-dihydro-1H-indenyl, R²¹-substituted or unsubstituted(2r,3as,5r,6as)-octahydro-2,5-methanopentyl, R²″-substituted orunsubstituted bicyclo[3.1.1]heptanyl, R²¹-substituted or unsubstitutedbicyclo[2.2.2]octanyl, R²¹-substituted or unsubstitutedspiro[2.5]octane, R²″-substituted or unsubstituted spiro[3.3]heptanyl,R²¹-substituted or unsubstituted spiro[5.5]undecanyl, R²¹-substituted orunsubstituted (1r,3r,5r,7r)-spiro[adamantane-2,1¹-cyclohexanyl],R²¹-substituted or unsubstituted(1R,3r,8S)-tricyclo[4.3.1.13,8]undecanyl, or R²¹-substituted orunsubstituted bicyclo[2.2.1]heptan-2-yl.

In embodiments, R⁷ is substituted cyclohexyl, substituted adamantyl,substituted 1,2,3,4-tetrahydronaphthalenyl, substituted2,3-dihydro-1H-indenyl, substituted(2r,3as,5r,6as)-octahydro-2,5-methanopentyl, substitutedbicyclo[3.1.1]heptanyl, substituted bicyclo[2.2.2]octanyl, substitutedspiro[2.5]octane, substituted spiro[3.3]heptanyl, substitutedspiro[5.5]undecanyl, substituted(1r,3r,5r,7r)-spiro[adamantane-2,1¹-cyclohexanyl], substituted(1R,3r,8S)-tricyclo[4.3.1.13,8]undecanyl, or substitutedbicyclo[2.2.1]heptan-2-yl. In embodiments, R⁷ is substituted cyclohexyl.In embodiments, R⁷ is substituted adamantly. In embodiments, R⁷ issubstituted 1,2,3,4-tetrahydronaphthalenyl. In embodiments, R⁷ issubstituted 2,3-dihydro-1H-indenyl, substituted(2r,3as,5r,6as)-octahydro-2,5-methanopentyl. In embodiments, R⁷ issubstituted bicyclo[3.1.1]heptanyl. In embodiments, IC is substitutedbicyclo[2.2.2]octanyl. In embodiments, R⁷ is substitutedspiro[2.5]octane. In embodiments, R⁷ is substituted spiro[3.3]heptanyl.In embodiments, R⁷ is substituted spiro[5.5]undecanyl. In embodiments,R⁷ is substituted (1r,3r,5r,70-spiro[adamantane-2,1′-cyclohexanyl]. Inembodiments, R⁷ is substituted (1R,3r,8S)-tricyclo[4.3. 1 .13,8]undecanyl. In embodiments, R⁷ is substitutedbicyclo[2.2.1]heptan-2-yl.

In embodiments, R⁷ is R²¹-substituted cyclohexyl, substituted adamantyl,R²¹-substituted 1,2,3,4-tetrahydronaphthalenyl, substituted2,3-dihydro-1H-indenyl, R²¹⁻-substituted(2r,3as,5r,6as)-octahydro-2,5-methanopentyl, R²¹-substitutedbicyclo[3.1.1]heptanyl, R²¹-substituted bicyclo[2.2.2]octanyl,R²¹-substituted spiro[2.5]octane, R²¹-substituted spiro[3.3]heptanyl,R²¹-substituted spiro[5.5]undecanyl, R²¹-substituted(1r,3r,5r,7r)-spiro[adamantane-2,1′-cyclohexanyl], R²¹-substituted(1R,3r,8S)-tricyclo[4.3.1.13,8]undecanyl, or R²¹-substitutedbicyclo[2.2.1]heptan-2-yl. In embodiments, R⁷ is R²¹-substitutedcyclohexyl. In embodiments, R⁷ is R²¹-substituted adamantly. Inembodiments, R⁷ is R²¹-substituted 1,2,3,4-tetrahydronaphthalenyl. Inembodiments, R⁷ is R²¹-substituted 2,3-dihydro-1H-indenyl,R²¹-substituted (2r,3as,5r,6as)-octahydro-2,5-methanopentyl. Inembodiments, R⁷ is R²¹-substituted bicyclo[3.1.1]heptanyl. Inembodiments, R⁷ is R²¹-substituted bicyclo[2.2.2]octanyl. Inembodiments, R⁷ is R²¹-substituted spiro[2.5]octane. In embodiments, R⁷is R²¹-substituted spiro[3.3]heptanyl. In embodiments, R⁷ isR²¹-substituted spiro[5.5]undecanyl. In embodiments, R⁷ isR²¹-substituted (1r,3r,5r,7r)-spiro[adamantane-2,1′-cyclohexanyl]. Inembodiments, R⁷ is R²¹-substituted (1R,3r,8S)-tricyclo[4.3 .1.13,8]undecanyl. In embodiments, R⁷ is R²¹-substitutedbicyclo[2.2.1]heptan-2-yl.

In embodiments, R⁷ is unsubstituted cyclohexyl, unsubstituted adamantyl,unsubstituted 1,2,3,4-tetrahydronaphthalenyl, unsubstituted2,3-dihydro-1H-indenyl, unsubstituted(2r,3as,5r,6as)-octahydro-2,5-methanopentyl, unsubstitutedbicyclo[3.1.1]heptanyl, unsubstituted bicyclo[2.2.2]octanyl,unsubstituted spiro[2.5]octane, unsubstituted spiro[3.3]heptanyl,unsubstituted spiro[5.5]undecanyl, unsubstituted(1r,3r,5r,7r)-spiro[adamantane-2,1 ′-cyclohexanyl], unsubstituted(1R,3r,8S)-tricyclo[4.3.1.13,8]undecanyl, or unsubstituted bicyclo[2.2.1]heptan-2-yl. In embodiments,

R⁷ is unsubtituted cyclohexyl. In embodiments, R⁷ is unsubstitutedadamantly. In embodiments, R⁷ is unsubstituted1,2,3,4-tetrahydronaphthalenyl. In embodiments, R⁷ is unsubstituted2,3-dihydro-1H-indenyl. In embodiments, R⁷ is unsubstituted(2r,3as,5r,6as)-octahydro-2,5-methanopentyl. In embodiments, R⁷ isunsubstituted bicyclo[3.1.1]heptanyl. In embodiments, R⁷ isunsubstituted bicyclo[2.2.2]octanyl. In embodiments, R⁷ is unsubstitutedspiro[2.5]octane. In embodiments, R⁷ is unsubstitutedspiro[3.3]heptanyl. In embodiments, R⁷ is unsubstitutedspiro[5.5]undecanyl. In embodiments, R⁷ is unsubstituted(1r,3r,5r,7r)-spiro[adamantane-2,1′-cyclohexanyl]. In embodiments, R⁷ isunsubstituted (1R,3r,88)-tricyclo[4.3.1.13,8]undecanyl. In embodiments,R⁷ is unsubstituted bicyclo[2.2.1]heptan-2-yl.

In embodiments, R⁷ is substituted or unsubstituted phenyl, naphthyl,pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl,pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl,pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl,benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl,isoquinolyl, quinoxalinyl, or quinolyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted phenyl, naphthyl,pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl,pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl,pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl,benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl,isoquinolyl, quinoxalinyl, or quinolyl.

In embodiments, R⁷ is substituted or unsubstituted benzimidazolyl,indolyl, or benzofuranyl. In embodiments, R⁷ is unsubstitutedbenzimidazolyl. In embodiments, R⁷ is unsubstituted indolyl. Inembodiments, R⁷ is unsubstituted benzofuranyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted benzimidazolyl,indolyl, or benzofuranyl. In embodiments, R⁷ is unsubstitutedbenzimidazolyl. In embodiments, R⁷ is unsubstituted indolyl. Inembodiments, R⁷ is unsubstituted benzofuranyl.

In embodiments, R⁷ is

In embodiments, R⁷ is substituted or unsubstituted naphthyl. Inembodiments, R⁷ is unsubstituted naphthyl.

In embodiments, R⁷ is

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In embodiments, R⁷ is cycloalkyl. In embodiments, R⁷ is monocycliccycloalkyl. In embodiments, R⁷ is bicyclic cycloalkyl. In embodiments,R⁷ is tricyclic cycloalkyl. In embodiments, R⁷ is bridged monocycliccycloalkyl. In embodiments, R⁷ is bridged bicyclic cycloalkyl. Inembodiments, R⁷ is bridged tricyclic cycloalkyl. In embodiments, R⁷ isfused bicyclic cycloalkyl. In embodiments, R⁷ is fused tricycliccycloalkyl.

In embodiments, R⁷ is cycloalkyl (e.g., C₅-C₆ cycloalkyl). Inembodiments, R⁷ is monocyclic cycloalkyl (e.g., C₅-C₆ cycloalkyl). Inembodiments, R⁷ is bicyclic cycloalkyl (e.g., C₉-C₁₁ cycloalkyl orC₇-C₁₂ cycloalkyl). In embodiments, R⁷ is tricyclic cycloalkyl (e.g.,C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). In embodiments, R⁷ is bridgedbicyclic cycloalkyl (e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). Inembodiments, R⁷ is bridged tricyclic cycloalkyl (e.g., C₉-C₁₁ cycloalkylor C₇-C₁₂ cycloalkyl). In embodiments, R⁷ is fused bicyclic cycloalkyl(e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). In embodiments, R⁷ isfused tricyclic cycloalkyl (e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂cycloalkyl).

In embodiments, R⁷ is substituted or unsubstituted fused bicycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). Inembodiments, R⁷ is substituted or unsubstituted C₇-C₁₂ fused bicycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₇-C₁₁fused bicyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C¹⁰ fused bicyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₇-C₉ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C₈ fused bicycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₈-C₁₁fused bicyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₈-C₁₀ fused bicyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₈-C₉ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₁₂ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₁₁ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C¹⁰ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₉ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₁₁ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C⁸-C₁₁ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₈-C₁₀ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₈-C₉ fused bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C₁₂ fused bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C₁₁ fused bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C¹⁰ fused bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C₉ fused bicyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C₈ fused bicycliccycloalkyl. In embodiments, R⁷ is unsubstituted C₈-C₁₁ fused bicycliccycloalkyl. In embodiments, R⁷ is unsubstituted C₈-C₁₀ fused bicycliccycloalkyl. In embodiments, R⁷ is unsubstituted C₈-C₉ fused bicycliccycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted fused bicycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₁₂ fusedbicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C7-CLL fused bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C¹⁰ fused bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₉ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₈fused bicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C⁸-C₁₁ fused bicyclic cycloalkyl. In embodiments, R⁷ isW^(I)-substituted or unsubstituted C₈-C₁₀ fused bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₈-C₉ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₂ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₁ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C¹⁰ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₉ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₈ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₁₁ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₁₀ fused bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₉ fused bicycliccycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted bridged bicycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). Inembodiments, R⁷ is substituted or unsubstituted C₇-C₁₂ bridged bicycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₇-C₁₁bridged bicyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C¹⁰ bridged bicyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₇-C₉ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C₁₁ bridged bicycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₈-C₁₁bridged bicyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₈-C₁₀ bridged bicyclic cycloalkyl. In embodiments, It⁷ issubstituted or unsubstituted C₈-C₉ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₁₂ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₁₁ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C¹⁰ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₉ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₈ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C8-C₁₁ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₈-C₁₀ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₈-C₉ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C₁₂ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C7-C₁₁ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C¹⁰ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C₉ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C₈ bridged bicycliccycloalkyl. In embodiments, R⁷ is unsubstituted C₈-C₁₁ bridged bicycliccycloalkyl. In embodiments, R⁷ is unsubstituted C₈-C₁₀ bridged bicycliccycloalkyl. In embodiments, R⁷ is unsubstituted C₈-C₉ bridged bicycliccycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted bridged bicycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl or C₇-C₁₂ cycloalkyl). Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₁₂ bridgedbicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C₁₁ bridged bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C₁₀ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₉ bridgedbicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C₈ bridged bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₈-C₁₁ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₈-C₁₀ bridgedbicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₈-C₉ bridged bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted C7-C₁₂ bridged bicyclic cycloalkyl. In embodiments, R⁷is R²¹-substituted C₇-C₁₁ bridged bicyclic cycloalkyl. In embodiments,R⁷ is R²¹-substituted C₇-C¹⁰ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted C₇-C₉ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted C₇-C₈ bridged bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted C⁸-C₁₁ bridged bicyclic cycloalkyl.In embodiments, R⁷ is R²¹-substituted C₈-C₁₂ bridged bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₉ bridged bicycliccycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted spirocyclic bicycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₇-C₁₂ cycloalkyl, or C₇-C₁₅cycloalkyl). In embodiments, R⁷ is substituted or unsubstituted C₇-C₁₅spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₁₂ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷is substituted or unsubstituted C₇-C₁₁ spirocyclic bicyclic cycloalkyl.In embodiments, R⁷ is substituted or unsubstituted C₇-C¹⁰ spirocyclicbicyclic cycloalkyl. In embodiments, R⁷ is substituted or unsubstitutedC₇-C₉ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted C₇-C₈spirocyclic bicyclic cycloalkyl. In embodiments,R⁷ is substituted or unsubstituted C₈-C₁₁ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₈-C₁₀spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₈-C₉ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷is substituted C₇-C₁₅ spirocyclic bicyclic cycloalkyl. In embodiments,R⁷ is substituted C₇-C₁₂ spirocyclic bicyclic cycloalkyl. Inembodiments, R⁷ is substituted C₇-C₁₁ spirocyclic bicyclic cycloalkyl.In embodiments, R⁷ is substituted C₇-C¹⁰ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is substituted C₇-C₉ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₁ spirocyclicbicyclic cycloalkyl. In embodiments, R⁷ is substituted C⁸-C₁₁spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ is substitutedC₈-C₁₀ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ issubstituted C₈-C₉ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₇-C₁₅ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷is unsubstituted C₇-C₁₂ spirocyclic bicyclic cycloalkyl. In embodiments,R⁷ is unsubstituted C₇-C₁₁ spirocyclic bicyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C¹⁰ spirocyclic bicyclic cycloalkyl.In embodiments, R⁷ is unsubstituted C₇-C₉ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₇-C₈spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ is unsubstitutedC⁸-C₁₁ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₁₀ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷is unsubstituted C₈-C₉ spirocyclic bicyclic cycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted spirocyclicbicyclic cycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₇-C₁₂ cycloalkyl, orC₇-C₁₅ cycloalkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C₁₅ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷is R²¹-substituted or unsubstituted C₇-C₁₂ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstitutedC₇-C₁₁ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C₁₀ spirocyclic bicyclic cycloalkyl.In embodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₉ spirocyclicbicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C₈ g spirocyclic bicyclic cycloalkyl. In embodiments,R⁷ is R²¹-substituted or unsubstituted C₈-C₁₁ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstitutedC₈-C₁₀ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C⁸-C₉ spirocyclic bicyclic cycloalkyl.In embodiments, R⁷ is R²¹-substituted C₇-C₁₅ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₂ spirocyclicbicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₁spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ is R²¹-substitutedC₇-C₁₀ spirocyclic bicyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted C₇-C₉ spirocyclic bicyclic cycloalkyl. In embodiments,R⁷ is R²¹-substituted C₇-C₈ spirocyclic bicyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted C₈-C₁₁ spirocyclic bicycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₁₀ spirocyclicbicyclic cycloalkyl. In embodiments,

R⁷ is R²¹-substituted C₈-C₉ spirocyclic bicyclic cycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted fused tricycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₇-C₁₂ cycloalkyl, or C₇-C₁₅cycloalkyl). In embodiments, R⁷ is substituted or unsubstituted C₇-C₁₅fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₁₂ fused tricyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₇-C₁₁ fused tricyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C¹⁰ fused tricycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₇-C₉fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₁₁ fused tricyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₈-C₁₁ fused tricyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₈-C₁₀ fused tricycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₈-C₉fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₅fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₂fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₁fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C¹⁰fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₉fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₈fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₈-C₁₁fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₈-C₁₀fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₈-C₉fused tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₁₅fused tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₁₂fused tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₁₁fused tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C¹⁰fused tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₉fused tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₁₁ fused tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₁₁ fused tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₁₀ fused tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₉ fused tricyclic cycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted fused tricycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₇-C₁₂ cycloalkyl, or C₇-C₁₅cycloalkyl). In embodiments, R⁷ is R²¹-substituted or unsubstitutedC₇-C₁₅ fused tricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted C₇-C₁₂ fused tricyclic cycloalkyl. In embodiments, R⁷is R²¹-substituted or unsubstituted C₇-C₁₁ fused tricyclic cycloalkyl.In embodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C¹⁰ fusedtricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C₉ fused tricyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C₁₁ fused tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₈-C₁₁ fusedtricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₈-C₁₀ fused tricyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted substituted or unsubstituted C₈-C₉ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₅ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₂ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₁ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C¹⁰ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₉ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₈ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₁₁ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₁₀ fused tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₉ fused tricycliccycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted bridged tricycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₇-C₁₂ cycloalkyl, or C₇-C₁₅cycloalkyl). In embodiments, R⁷ is substituted or unsubstituted C₇-C₁₅bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₁₂ bridged tricyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₇-C₁₁ bridged tricyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C¹⁰ bridged tricycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstitutedC₇-C₉bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₈ bridged tricyclic cycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₈-C₁₁ bridged tricyclic cycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₈-C₁₀ bridged tricycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₈-C₉bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₅bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₂bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₁bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C¹⁰bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₉bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₇-C₈bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C⁸-C₁₁bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₈-C₁₀bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted C₈-C₉bridged tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₁₅bridged tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₁₂bridged tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₁₁bridged tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C¹⁰bridged tricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₇-C₉bridged tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₇-C₈ bridged tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₁₁ bridged tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₁₀ bridged tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₉ bridged tricyclic cycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted bridged tricycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₇-C₁₂ cycloalkyl, or C₇-C₁₅cycloalkyl). In embodiments, R⁷ is R²¹-substituted or unsubstitutedC₇-C₁₅ bridged tricyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C₁₂ bridged tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₁₁ bridgedtricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C¹⁰ bridged tricyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C₉ bridged tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₈ bridgedtricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₈-C₁₁bridged tricyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₈-C₁₀ bridged tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₈-C₉ bridgedtricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₁₅bridged tricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substitutedC₇-C₁₂ bridged tricyclic cycloalkyl. In embodiments, R⁷ isR²¹-substituted C⁷-C₁₁ bridged tricyclic cycloalkyl. In embodiments, R⁷is R²¹-substituted C₇-C¹⁰ bridged tricyclic cycloalkyl. In embodiments,R⁷ is R²¹-substituted C₇-C₉ bridged tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted C₇-C₈ bridged tricyclic cycloalkyl.In embodiments, R⁷ is R²¹-substituted C₈-C₁₁ bridged tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₁₀ bridgedtricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted C₈-C₉bridged tricyclic cycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted spirocyclic tricycliccycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₉-C₁₅ cycloalkyl, or C₁₂-C₁₈cycloalkyl). In embodiments, R⁷ is substituted or unsubstituted C₁₂-C₁₈spirocyclic tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₉-C₁₅ spirocyclic tricyclic cycloalkyl. In embodiments,R⁷ is substituted or unsubstituted C₉-C₁₂ spirocyclic tricycliccycloalkyl. In embodiments, R⁷ is substituted or unsubstituted C₉-C₁₁spirocyclic tricyclic cycloalkyl. In embodiments, R⁷ is substituted orunsubstituted C₁₂-C₁₈ spirocyclic tricyclic cycloalkyl. In embodiments,R⁷ is substituted C₉-C₁₅ spirocyclic tricyclic cycloalkyl. Inembodiments, R⁷ is substituted C₉-C₁₂ spirocyclic tricyclic cycloalkyl.In embodiments, R⁷ is substituted C₉-C₁₁ spirocyclic tricycliccycloalkyl. In embodiments, R⁷ is substituted C₉-C₁₀ spirocyclictricyclic cycloalkyl. In embodiments, R⁷ is unsubstituted C₁₂-C₁₈spirocyclic tricyclic cycloalkyl. In embodiments, R⁷ is unsubstitutedC₉-C₁₅ spirocyclic tricyclic cycloalkyl. In embodiments, R⁷ isunsubstituted C₉-C₁₂ spirocyclic tricyclic cycloalkyl. In embodiments,R⁷ is unsubstituted C₉-C₁₁ spirocyclic tricyclic cycloalkyl. Inembodiments, R⁷ is unsubstituted C₉-C₁₀ spirocyclic tricycliccycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted spirocyclictricyclic cycloalkyl (e.g., C₉-C₁₁ cycloalkyl, C₉-C₁₅ cycloalkyl, orC₁₂-C₁₈ cycloalkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted C₁₂-C₁₈ spirocyclic tricyclic cycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted C₉-C₁₅spirocyclic tricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted C₉-C₁₂ spirocyclic tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted C₉-C₁₁ spirocyclictricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₁₂-C₁₈ spirocyclic tricyclic cycloalkyl. In embodiments,R⁷ is R²¹-substituted C₉-C₁₅ spirocyclic tricyclic cycloalkyl. Inembodiments, R⁷ is R²¹-substituted C₉-C₁₂ spirocyclic tricycliccycloalkyl. In embodiments, R⁷ is R²¹-substituted C₉-C₁₁ spirocyclictricyclic cycloalkyl. In embodiments, R⁷ is R²¹-substituted C₉-C₁₀spirocyclic tricyclic cycloalkyl.

In embodiments, R⁷ is a C₉-C₁₄ fused bicyclic aryl. In embodiments, R⁷is a C₉ fused bicyclic aryl. In embodiments, R⁷ is a C₁₀ fused bicyclicaryl. In embodiments, R⁷ is a C₁₁ fused bicyclic aryl. In embodiments,R⁷ is a C₁₂ fused bicyclic aryl. In embodiments, R⁷ is a CH fusedbicyclic aryl. In embodiments, R⁷ is a C₁₄ fused bicyclic aryl. Inembodiments, R⁷ is a fused bicyclic aryl wherein a cycloalkyl ring isfused to a phenyl group. In embodiments, R⁷ is a fused bicyclic arylwherein a cycloalkyl ring is fused to an aryl group. In embodiments, R⁷is an 8 to 12 membered fused bicyclic heteroaryl. In embodiments, R⁷ isan 8 to 10 membered fused bicyclic heteroaryl. In embodiments, R⁷ is afused bicyclic heteroaryl wherein a cycloalkyl ring is fused to aheteroaryl group. In embodiments, R⁷ is a fused bicyclic heteroarylwherein a cycloalkyl ring is fused to a 6-membered heteroaryl group. Inembodiments, R⁷ is a fused bicyclic heteroaryl wherein a cycloalkyl ringis fused to a 5-membered heteroaryl group. In embodiments, R⁷ is an8-membered fused bicyclic heteroaryl wherein a cycloalkyl is fused to aheteroaryl ring with three heteroatoms. In embodiments, R⁷ is a9-membered fused bicyclic heteroaryl wherein a cycloalkyl is fused to aheteroaryl ring with two heteroatoms. In embodiments, R⁷ is a10-membered fused bicyclic heteroaryl wherein a cycloalkyl is fused to aheteroaryl ring with one heteroatom. In embodiments, R⁷ is an 8-memberedfused bicyclic heteroaryl wherein a cycloalkyl is fused to a heteroarylring with three heteroatoms. In embodiments, R⁷ is a 9-membered fusedbicyclic heteroaryl wherein a cycloalkyl is fused to a heteroaryl ringwith two heteroatoms. In embodiments, R⁷ is a 10-membered fused bicyclicheteroaryl wherein a cycloalkyl is fused to a heteroaryl ring with oneheteroatom.

In embodiments, R⁷ is heterocycloalkyl. In embodiments, R⁷ is monocyclicheterocycloalkyl. In embodiments, R⁷ is bicyclic heterocycloalkyl. Inembodiments, R⁷ is tricyclic heterocycloalkyl. In embodiments, R⁷ isbridged monocyclic heterocycloalkyl. In embodiments, R⁷ is bridgedbicyclic heterocycloalkyl. In embodiments, R⁷ is bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is fused bicyclic heterocycloalkyl.In embodiments, R⁷ is fused tricyclic heterocycloalkyl.

In embodiments, R⁷ is heterocycloalkyl (e.g., C₅-C₆ heterocycloalkyl).In embodiments, R⁷ is monocyclic heterocycloalkyl (e.g., C₅-C₆heterocycloalkyl). In embodiments, R⁷ is bicyclic heterocycloalkyl(e.g., C₉-C₁₁ heterocycloalkyl or C₇-C₁₂ heterocycloalkyl). Inembodiments, R⁷ is tricyclic heterocycloalkyl (e.g., C₉-C₁₁heterocycloalkyl or C₇-C₁₂ heterocycloalkyl). In embodiments, R⁷ isbridged bicyclic heterocycloalkyl (e.g., C₉-C₁₁ heterocycloalkyl orC₇-C₁₂ heterocycloalkyl). In embodiments, R⁷ is bridged tricyclicheterocycloalkyl (e.g., C₉-C₁₁ heterocycloalkyl or C₇-C₁₂heterocycloalkyl). In embodiments, R⁷ is fused bicyclic heterocycloalkyl(e.g., C₉-C₁₁ heterocycloalkyl or C₇-C₁₂ heterocycloalkyl). Inembodiments, R⁷ is fused tricyclic heterocycloalkyl (e.g., C₉-C₁₁heterocycloalkyl or C₇-C₁₂ heterocycloalkyl).

In embodiments, R⁷ is a C₉-C₁₀ fused bicyclic heterocycloalkyl. Inembodiments, R⁷ is a C₉ fused bicyclic heterocycloalkyl. In embodiments,R⁷ is a C₁₀ fused bicyclic heterocycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted fused bicyclicheterocycloalkyl (e.g., C₉-C₁₁ heterocycloalkyl or C₇-C₁₂heterocycloalkyl). In embodiments, R⁷ is substituted or unsubstitutedC₇-C₁₂ fused bicyclic heterocycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₇-C₁₁ fused bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted C₇-C¹⁰ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted or unsubstitutedC₇-C₉ fused bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted C₇-C₁₁ fused bicyclic heterocycloalkyl. In embodiments,R⁷ is substituted or unsubstituted C⁸-C₁₁ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted or unsubstitutedC₈-C₁₀ fused bicyclic heterocycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted C₈-C₉ fused bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted C7-C₁₂ fused bicyclic heterocycloalkyl.In embodiments, R⁷ is substituted C₇-C₁₁ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted C₇-C¹⁰ fusedbicyclic heterocycloalkyl. In embodiments, R⁷ is substituted C₇-C₉ fusedbicyclic heterocycloalkyl. In embodiments, R⁷ is substituted C₇-C₁₁fused bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedC₈-C₁₁ fused bicyclic heterocycloalkyl. In embodiments, R⁷ issubstituted C₈-C₁₀ fused bicyclic heterocycloalkyl. In embodiments, R⁷is substituted C₈-C₉ fused bicyclic heterocycloalkyl. In embodiments, R⁷is unsubstituted C₇-C₁₂ fused bicyclic heterocycloalkyl. In embodiments,R⁷ is unsubstituted C₇-C₁₁ fused bicyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted C₇-C¹⁰ fused bicyclic heterocycloalkyl.In embodiments, R⁷ is unsubstituted C₇-C₉ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted or unsubstitutedC₇-C₈ fused bicyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted C₈-C₁₁ fused bicyclic heterocycloalkyl. In embodiments, R⁷is unsubstituted C₈-C₁₀ fused bicyclic heterocycloalkyl. In embodiments,R⁷ is unsubstituted C₈-C₉ fused bicyclic heterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted fused bicyclicheterocycloalkyl (e.g., C₉-C₁₁ heterocycloalkyl or C₇-C₁₂heterocycloalkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted C₇-C₁₂ fused bicyclic heterocycloalkyl. In embodiments, R⁷is R²¹-substituted or unsubstituted C₇-C₁₁ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstitutedC₇-C¹⁰ fused bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted C₇-C₉ fused bicyclic heterocycloalkyl.In embodiments, R⁷ is R²¹-substituted or unsubstituted C₇-C₁₁ fusedbicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted C₈-C₁₁ fused bicyclic heterocycloalkyl. In embodiments, R⁷is R²¹-substituted or unsubstituted C₈-C₁₀ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstitutedC₈-C₉ fused bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted C₇-C₁₂ fused bicyclic heterocycloalkyl. In embodiments,R⁷ is R²¹-substituted C₇-C₁₁ fused bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted C₇-C₁₀ fused bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₉ fusedbicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted C₇-C₈fused bicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedC₈-C₁₁ fused bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted C₈-C₁₀ fused bicyclic heterocycloalkyl. In embodiments,R⁷ is R²¹-substituted C₈-C₉ fused bicyclic heterocycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted bridged bicyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl or 7 to 12membered heterocycloalkyl). In embodiments, R⁷ is substituted orunsubstituted 7 to 12 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 11 membered bridgedbicyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 10 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 9 membered bridgedbicyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 8 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 8 to 11 membered bridgedbicyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 8 to 10 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 8 to 9 membered bridgedbicyclic heterocycloalkyl. In embodiments, R⁷ is substituted 7 to 12membered bridged bicyclic heterocycloalkyl. In embodiments, R⁷ issubstituted 7 to 11 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 7 to 10 membered bridged bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted 7 to 9 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is substituted 7to 8 membered bridged bicyclic heterocycloalkyl. In embodiments, R⁷ issubstituted 8 to 11 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 8 to 10 membered bridged bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted 8 to 9 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 7to 12 membered bridged bicyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 7 to 11 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 7 to 10 membered bridged bicyclicheterocycloalkyl. In embodiments, R⁷ is unsubstituted 7 to 9 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 8 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 8 to 11 membered bridged bicyclicheterocycloalkyl. In embodiments, R⁷ is unsubstituted 8 to 10 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 8to 9 membered bridged bicyclic heterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted bridged bicyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl or 7 to 12membered heterocycloalkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted 7 to 12 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 11 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 7 to 10 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 9 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 7 to 8 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 8 to 11 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 8 to 10 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 8 to 9 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted7 to 12 membered bridged bicyclic heterocycloalkyl. In embodiments, R⁷is R²¹-substituted 7 to 11 membered bridged bicyclic heterocycloalkyl.In embodiments, R⁷ is R²¹-substituted 7 to 10 membered bridged bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 7 to 9 memberedbridged bicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted7 to 8 membered bridged bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 8 to 11 membered bridged bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted 8 to 10 membered bridged bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 8 to 9 memberedbridged bicyclic heterocycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted spirocyclic bicyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 7 to 12membered heterocycloalkyl, or 7 to 15 membered heterocycloalkyl). Inembodiments, R⁷ is substituted or unsubstituted 7 to 15 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted 7 to 12 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is substituted or unsubstituted 7 to 11 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted 7 to 10 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is substituted or unsubstituted 7 to 9 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted 7 to 8 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is substituted or unsubstituted 8 to 11 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted 8 to 10 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is substituted or unsubstituted 8 to 9 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substituted7 to 15 membered spirocyclic bicyclic heterocycloalkyl. In embodiments,R⁷ is substituted 7 to 12 membered spirocyclic bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted 7 to 11 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substituted7 to 10 membered spirocyclic bicyclic heterocycloalkyl. In embodiments,R⁷ is substituted 7 to 9 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is substituted 7 to 8 membered spirocyclic bicyclicheterocycloalkyl. In embodiments, R⁷ is substituted 8 to 11 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substituted8 to 10 membered spirocyclic bicyclic heterocycloalkyl. In embodiments,R⁷ is substituted 8 to 9 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is unsubstituted 7 to 15 membered spirocyclicbicyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 7 to 12membered spirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 7 to 11 membered spirocyclic bicyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 7 to 10 membered spirocyclic bicyclicheterocycloalkyl. In embodiments, R⁷ is unsubstituted 7 to 9 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ is substitutedor unsubstituted 7 to 8 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is unsubstituted 8 to 11 membered spirocyclicbicyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 8 to 10membered spirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 8 to 9 membered spirocyclic bicyclic heterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted spirocyclicbicyclic heterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 7 to12 membered heterocycloalkyl, or 7 to 15 membered heterocycloalkyl). Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 15 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted 7 to 12 membered spirocyclic bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted7 to 11 membered spirocyclic bicyclic heterocycloalkyl. In embodiments,R⁷ is R²¹-substituted or unsubstituted 7 to 10 membered spirocyclicbicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted 7 to 9 membered spirocyclic bicyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 8 memberedspirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted 8 to 11 membered spirocyclic bicyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted8 to 10 membered spirocyclic bicyclic heterocycloalkyl. In embodiments,R⁷ is R²¹-substituted or unsubstituted 8 to 9 membered spirocyclicbicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 7 to 15membered spirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 7 to 12 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is 10-substituted 7 to 11 membered spirocyclicbicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 7 to 10membered spirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 7 to 9 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is R²¹-substituted 7 to 8 membered spirocyclicbicyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 8 to11membered spirocyclic bicyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 8 to 10 membered spirocyclic bicyclic heterocycloalkyl.In embodiments, R⁷ is R²¹-substituted 8 to 9 membered spirocyclicbicyclic heterocycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted fused tricyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 7 to 12membered heterocycloalkyl, or 7 to 15 membered heterocycloalkyl). Inembodiments, R⁷ is substituted or unsubstituted 7 to 15 membered fusedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 12 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 11 membered fusedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 10 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 9 membered fusedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 8 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 8 to 11 membered fusedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 8 to 10 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 8 to 9 membered fusedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted 7 to 15membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ issubstituted 7 to 12 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 7 to 11 membered fused tricyclicheterocycloalkyl. In embodiments, R⁷ is substituted 7 to 10 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is substituted 7 to9 membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ issubstituted 7 to 8 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 8 to 11 membered fused tricyclicheterocycloalkyl. In embodiments, R⁷ is substituted 8 to 10 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is substituted 8 to9 membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 7 to 15 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 7 to 12 membered fused tricyclicheterocycloalkyl. In embodiments, R⁷ is unsubstituted 7 to 11 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 7to 10 membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 7 to 9 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 8 membered fusedtricyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 8 to 11membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 8 to 10 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 8 to 9 membered fused tricyclicheterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted fused tricyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 7 to 12membered heterocycloalkyl, or 7 to 15 membered heterocycloalkyl). Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 15 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 7 to 12 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 11 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 7 to 10 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 9 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 7 to 8 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 8 to 11 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substitutedor unsubstituted 8 to 10 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted or unsubstituted 8 to 9 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted7 to 15 membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 7 to 12 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted 7 to 11 membered fused tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 7 to 10 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted7 to 9 membered fused tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 7 to 8 membered fused tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted 8 to 11 membered fused tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 8 to 10 memberedfused tricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted8 to 9 membered fused tricyclic heterocycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted bridged tricyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 7 to 12membered heterocycloalkyl, or 7 to 15 membered heterocycloalkyl). Inembodiments, R⁷ is substituted or unsubstituted 7 to 15 membered bridgedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 12 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 11 membered bridgedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 10 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 9 membered bridgedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 7 to 8 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 8 to 11 membered bridgedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 8 to 10 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 8 to 9 membered bridgedtricyclic heterocycloalkyl. In embodiments, R⁷ is substituted 7 to 15membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷ issubstituted 7 to 12 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 7 to 11 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is substituted 7 to 10 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ is substituted 7to 9 membered f bridged used tricyclic heterocycloalkyl. In embodiments,R⁷ is substituted 7 to 8 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 8 to 11 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is substituted 8 to 10 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ is substituted 8to 9 membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 7 to 15 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 7 to 12 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is unsubstituted 7 to 11 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted7 to 10 membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷is unsubstituted 7 to 9 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted or unsubstituted 7 to 8 membered bridgedtricyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 8 to 11membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 8 to 10 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is unsubstituted 8 to 9 membered bridged tricyclicheterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted bridged tricyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 7 to 12membered heterocycloalkyl, or 7 to 15 membered heterocycloalkyl). Inembodiments, R⁷ is R²¹-substituted or unsubstituted 7 to 15 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted 7 to 12 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted7 to 11 membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷is R²¹-substituted or unsubstituted 7 to 10 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted7 to 9 membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷is R²¹-substituted or unsubstituted 7 to 8 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted8 to 11 membered bridged tricyclic heterocycloalkyl. In embodiments, R⁷is W^(I)-substituted or unsubstituted 8 to 10 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is W^(I)-substituted orunsubstituted 8 to 9 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted 7 to 15 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 7 to 12 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 7 to 11 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted 7 to 10 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 7 to 9 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 7 to 8 membered bridged tricyclic heterocycloalkyl. Inembodiments, R⁷ is R²¹-substituted 8 to 11 membered bridged tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 8 to 10 memberedbridged tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted 8 to 9 membered bridged tricyclic heterocycloalkyl.

In embodiments, R⁷ is substituted or unsubstituted spirocyclic tricyclicheterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 9 to 15membered heterocycloalkyl, or 12 to 18 membered heterocycloalkyl). Inembodiments, R⁷ is substituted or unsubstituted 12 to 18 memberedspirocyclic tricyclic heterocycloalkyl. In embodiments, R⁷ issubstituted or unsubstituted 9 to 15 membered spirocyclic tricyclicheterocycloalkyl. In embodiments, R⁷ is substituted or unsubstituted 9to 12 membered spirocyclic tricyclic heterocycloalkyl. In embodiments,R⁷ is substituted or unsubstituted 9 to 11 membered spirocyclictricyclic heterocycloalkyl. In embodiments, R⁷ is substituted orunsubstituted 12 to 18 membered spirocyclic tricyclic heterocycloalkyl.In embodiments, R⁷ is substituted 9 to 15 spirocyclic tricyclicheterocycloalkyl. In embodiments, R⁷ is substituted 9 to 12 memberedspirocyclic tricyclic heterocycloalkyl. In embodiments, R⁷ issubstituted 9 to 11 membered spirocyclic tricyclic heterocycloalkyl. Inembodiments, R⁷ is substituted 9 to 10 membered spirocyclic tricyclicheterocycloalkyl. In embodiments, R⁷ is unsubstituted 12 to 18 memberedspirocyclic tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 9 to 15 membered spirocyclic tricyclic heterocycloalkyl.In embodiments, R⁷ is unsubstituted 9 to 12 membered spirocyclictricyclic heterocycloalkyl. In embodiments, R⁷ is unsubstituted 9 to 11membered spirocyclic tricyclic heterocycloalkyl. In embodiments, R⁷ isunsubstituted 9 to 10 membered spirocyclic tricyclic heterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted or unsubstituted spirocyclictricyclic heterocycloalkyl (e.g., 9 to 11 membered heterocycloalkyl, 9to 15 membered heterocycloalkyl, or 12 to 18 membered heterocycloalkyl).In embodiments, R⁷ is R²¹-substituted or unsubstituted 12 to 18 memberedspirocyclic tricyclic heterocycloalkyl. In embodiments, R⁷ isR²¹-substituted or unsubstituted 9 to 15 membered spirocyclic tricyclicheterocycloalkyl. In embodiments, R⁷ is R²¹-substituted or unsubstituted9 to 12 membered spirocyclic tricyclic heterocycloalkyl. In embodiments,R⁷ is R²¹-substituted or unsubstituted 9 to 11 membered spirocyclictricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted orunsubstituted 12 to 18 membered spirocyclic tricyclic heterocycloalkyl.In embodiments, R⁷ is R²¹-substituted 9 to 15 membered spirocyclictricyclic heterocycloalkyl.

In embodiments, R⁷ is R²¹-substituted 9 to 12 membered spirocyclictricyclic heterocycloalkyl. In embodiments, R⁷ is R²¹-substituted 9 to11 membered spirocyclic tricyclic heterocycloalkyl. In embodiments, R⁷is R²¹-substituted 9 to 10 membered spirocyclic tricyclicheterocycloalkyl.

In embodiments, R⁷ is a C₉-C₁₀ fused bicyclic aryl. In embodiments, R⁷is a C₉ fused bicyclic aryl. In embodiments, R⁷ is a C₁₀ fused bicyclicaryl. In embodiments, R⁷ is a fused bicyclic aryl wherein aheterocycloalkyl ring is fused to a phenyl group. In embodiments, R⁷ isa fused bicyclic aryl wherein a heterocycloalkyl ring is fused to anaryl group. In embodiments, R⁷ is a C₆-C₈ used bicyclic heteroaryl. Inembodiments, R⁷ is a C₇-C₉ fused bicyclic heteroaryl. In embodiments, R⁷is a fused bicyclic heteroaryl wherein a heterocycloalkyl ring is fusedto a heteroaryl group. In embodiments, R⁷ is a fused bicyclic heteroarylwherein a heterocycloalkyl ring is fused to a 6-membered heteroarylgroup. In embodiments, R⁷ is a fused bicyclic heteroaryl wherein aheterocycloalkyl ring is fused to a 5-membered heteroaryl group. Inembodiments, R⁷ is a C₆ fused bicyclic heteroaryl wherein aheterocycloalkyl is fused to a heteroaryl ring with three heteroatoms.In embodiments, R⁷ is a C₇ fused bicyclic heteroaryl wherein aheterocycloalkyl is fused to a heteroaryl ring with two heteroatoms. Inembodiments, R⁷ is a C₈ fused bicyclic heteroaryl wherein aheterocycloalkyl is fused to a heteroaryl ring with one heteroatom. Inembodiments, R⁷ is a C₇ fused bicyclic heteroaryl wherein aheterocycloalkyl is fused to a heteroaryl ring with three heteroatoms.In embodiments, R⁷ is a C₈ fused bicyclic heteroaryl wherein aheterocycloalkyl is fused to a heteroaryl ring with two heteroatoms. Inembodiments, R⁷ is a C₉ fused bicyclic heteroaryl wherein aheterocycloalkyl is fused to a heteroaryl ring with one heteroatom.

In embodiments, R⁷ is cycloalkyl and L² is a bond. In embodiments, R⁷ ismonocyclic cycloalkyl and L² is a bond. In embodiments, R⁷ is bicycliccycloalkyl and L² is a bond. In embodiments, R⁷ is tricyclic cycloalkyland L² is a bond. In embodiments, R⁷ is bridged monocyclic cycloalkyland L² is a bond. In embodiments, R⁷ is bridged bicyclic cycloalkyl andL² is a bond. In embodiments, R⁷ is bridged tricyclic cycloalkyl and L²is a bond. In embodiments, R⁷ is fused bicyclic cycloalkyl and L² is abond. In embodiments, R⁷ is fused tricyclic cycloalkyl and L² is a bond.

In embodiments, R⁷ is cycloalkyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is monocyclic cycloalkyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is bicyclic cycloalkyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is tricyclic cycloalkyl and L² is C₁-C₃ alkylene.

In embodiments, R⁷ is bridged monocyclic cycloalkyl and L² is C1-C₃alkylene. In embodiments, R⁷ is bridged bicyclic cycloalkyl and L² isC₁-C₃ alkylene. In embodiments, R⁷ is bridged tricyclic cycloalkyl andL² is C₁-C₃ alkylene. In embodiments, R⁷ is fused bicyclic cycloalkyland L² is C₁-C₃ alkylene. In embodiments, R⁷ is fused tricycliccycloalkyl and L² is C₁-C₃ alkylene.

In embodiments, R⁷ is substituted or unsubstituted adamantyl and L² is abond. In embodiments, R⁷ is substituted or unsubstituted adamantyl andL² is C₁-C₃ alkylene. In embodiments, R⁷ is substituted or unsubstitutedtetrahydronaphthyl and L² is a bond. In embodiments, R⁷ is substitutedor unsubstituted tetrahydronaphthyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is substituted or unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is a bond. Inembodiments, R⁷ is substituted or unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is substituted or unsubstituted dihydroindenyl and L² isa bond. In embodiments, R⁷ is substituted or unsubstituteddihydroindenyl and L² is C₁-C₃ alkylene. In embodiments, R⁷ issubstituted or unsubstituted bicyclo[3.3.1]heptanyl and L² is a bond. Inembodiments, R⁷ is substituted or unsubstituted bicyclo[3.3.1]heptanyland L² is C₁-C₃ alkylene. In embodiments, R⁷ is substituted orunsubstituted 2,3-dihydro-1H-indenyl and L² is a bond. In embodiments,R⁷ is substituted or unsubstituted 2,3-dihydro-1H-indenyl and L² isC₁-C₃ alkylene.

In embodiments, R⁷ is substituted adamantyl and L² is a bond. Inembodiments, R⁷ is substituted adamantyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is substituted tetrahydronaphthyl and L² is a bond. Inembodiments, R⁷ is substituted tetrahydronaphthyl and L² is C₁-C₃alkylene. In embodiments, R⁷ is substituted 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is a bond. In embodiments, R⁷ is substituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is C₁-C₃ alkylene.Inembodiments, R⁷ is substituted dihydroindenyl and L² is a bond. Inembodiments, R⁷ is substituted dihydroindenyl and L² is C₁-C₃ alkylene.In embodiments, R⁷ is substituted bicyclo[3.3.1]heptanyl and L² is abond. In embodiments, R⁷ is substituted bicyclo[3.3.1]heptanyl and L² isC₁-C₃ alkylene. In embodiments, R⁷ is substituted 2,3-dihydro-1H-indenyland L² is a bond. In embodiments, R⁷ is substituted2,3-dihydro-1H-indenyl and L² is CI-C₃ alkylene. In embodiments, R⁷ isunsubstituted adamantyl and L² is a bond. In embodiments, R⁷ isunsubstituted adamantyl and L² is C₁-C₃ alkylene. In embodiments, R⁷ isunsubstituted tetrahydronaphthyl and L² is a bond. In embodiments, R⁷ isunsubstituted tetrahydronaphthyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is a bond.

In embodiments, R⁷ is unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is substituted or unsubstituted dihydroindenyl and L² isa bond. In embodiments, R⁷ is substituted or unsubstituteddihydroindenyl and L² is C₁-C₃ alkylene. In embodiments, R⁷ issubstituted or unsubstituted bicyclo[3.3.1]heptanyl and L² is a bond. Inembodiments, R⁷ is substituted or unsubstituted bicyclo[3.3.1]heptanyland L² is C₁-C₃ alkylene. In embodiments, R⁷ is unsubstituted2,3-dihydro-1H-indenyl and L² is a bond. In embodiments, R⁷ isunsubstituted 2,3-dihydro-1H-indenyl and L² is C1-C₃ alkylene.

In embodiments, R⁷ is R²¹-substituted or unsubstituted adamantyl and L²is a bond. In embodiments, R⁷ is R²¹-substituted or unsubstitutedadamantyl and L² is C₁-C₃ alkylene.

In embodiments, R⁷ is R²¹-substituted or unsubstitutedtetrahydronaphthyl and L² is a bond. In embodiments, R⁷ isR²¹-substituted or unsubstituted tetrahydronaphthyl and L² is C₁-C₃alkylene. In embodiments, R⁷ is R²¹-substituted or unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is a bond. Inembodiments, R⁷ is R²¹-substituted or unsubstituted6,7,8,9-tetrahydro—SH,-benzo[7]annulenyl, and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is

R²¹-substituted or unsubstituted dihydroindenyl and L² is a bond. Inembodiments, R⁷ is R²¹-substituted or unsubstituted dihydroindenyl andL² is C₁-C₃ alkylene. In embodiments, R⁷ is R²¹-substituted orunsubstituted bicyclo[3.3.1]heptanyl and L² is a bond. In embodiments,R⁷ is R²¹-substituted or unsubstituted bicyclo[3.3.1]heptanyl and L² isC₁-C₃ alkylene. In embodiments, R⁷ is R²¹-substituted or unsubstituted2,3-dihydro-1H-indenyl and L² is a bond.

In embodiments, R⁷ is R²¹-substituted or unsubstituted2,3-dihydro-1H-indenyl and L² is C₁-C₃ alkylene.

In embodiments, R⁷ is R²¹-substituted adamantyl and L² is a bond. Inembodiments, R⁷ is R²¹-substituted adamantyl and L² is C₁-C₃ alkylene.In embodiments, R⁷ is R²¹-substituted tetrahydronaphthyl and L² is abond. In embodiments, R⁷ is R²¹-substituted tetrahydronaphthyl and L² isC₁-C₃ alkylene. In embodiments, R⁷ is R²¹-substituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is a bond. Inembodiments, R⁷ is R²¹-substituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is R²¹-substituted dihydroindenyl and L² is a bond. Inembodiments, R⁷ is R²¹-substituted dihydroindenyl and L² is C₁-C₃alkylene. In embodiments, R⁷ is R²¹-substituted bicyclo[3.3.1]heptanyland L² is a bond. In embodiments, R⁷ is R²¹-substitutedbicyclo[3.3.1]heptanyl and L² is C₁-C₃ alkylene. In embodiments, R⁷ isR²¹-substituted 2,3-dihydro1H-indenyl and L² is a bond. In embodiments,R⁷ is R²¹-substituted 2,3-dihydro-1H-indenyl and L² is C₁-C₃ alkylene.In embodiments, R⁷ is unsubstituted adamantyl and L² is a bond. Inembodiments, R⁷ is unsubstituted adamantyl and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is unsubstituted tetrahydronaphthyl and L² is a bond. Inembodiments, R⁷ is unsubstituted tetrahydronaphthyl and L² is C₁-C₃alkylene. In embodiments, R⁷ is unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is a bond. Inembodiments, R⁷ is unsubstituted6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, and L² is C₁-C₃ alkylene. Inembodiments, R⁷ is R²¹-substituted or unsubstituted dihydroindenyl andL² is a bond. In embodiments, R⁷ is R²¹-substituted or unsubstituteddihydroindenyl and L² is C₁-C₃ alkylene. In embodiments, R⁷ isR²¹-substituted or unsubstituted bicyclo[3.3.1]heptanyl and L² is abond. In embodiments, R⁷ is R²¹-substituted or unsubstitutedbicyclo[3.3.1]heptanyl and L² is C₁-C₃ alkylene. In embodiments, R⁷ isunsubstituted 2,3-dihydro-1H-indenyl and L² is a bond. In embodiments,R⁷ is unsubstituted 2,3-dihydro-1H-indenyl and L² is C₁-C₃ alkylene.

In embodiments, R²¹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—Cl₃CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl1, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NIANH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂C₁,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R²²—substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²²-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²²-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²²-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²¹ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²¹ is independently oxo. In embodiments, R²¹ isindependently halogen. In embodiments, R²¹ is independently —F. Inembodiments, R²¹ is independently —Cl. In embodiments, R²¹ isindependently —Br. In embodiments, R²¹ is independently —I. Inembodiments, R²¹ is independently —CCl₃. In embodiments, R²¹ isindependently —CBr₃. In embodiments, R²¹ is independently —CF₃. Inembodiments, R²¹ is independently —CI₃. In embodiments, R²¹ isindependently CHCl₂. In embodiments, R²¹ is independently —CHBr₂. Inembodiments, R²¹ is independently —CHF₂. In embodiments, R²¹ isindependently —CHI₂. In embodiments, R²¹ is independently —CH₂Cl Inembodiments, R²¹ is independently —CH₂Br. In embodiments, R²¹ isindependently —CH₂F. In embodiments, R²¹ is independently —CH₂I. Inembodiments, R²¹ is independently —CN. In embodiments, R²¹ isindependently —OH. In embodiments, R²¹ is independently —NH₂. Inembodiments, R²¹ is independently —COOH. In embodiments, R²¹ isindependently —CONH₂. In embodiments, R²¹ is independently —NO₂. Inembodiments, R²¹ is independently —SH. In embodiments, R²¹ isindependently —SO₃H. In embodiments, R²¹ is independently —SO₄H. Inembodiments, R²¹ is independently —SO₂NH₂. In embodiments, R²¹ isindependently NHNH₂. In embodiments, R²¹ is independently —ONH₂. Inembodiments, R²¹ is independently NHC(O)NHNH₂. In embodiments, R²¹ isindependently NHC(O)NH₂. In embodiments, R²¹ is independently —NHSO₂H.In embodiments, R²¹ is independently —NHC(O)H. In embodiments, R²¹ isindependently —NHC(O)OH. In embodiments, R²¹ is independently —NHOH. Inembodiments, R²¹ is independently —OCCl₃. In embodiments, R²¹ isindependently —OCF₃. In embodiments, R²¹ is independently —OCBr₃. Inembodiments, R²¹ is independently —OCI₃. In embodiments, R²¹ isindependently —OCHCl₂. In embodiments, R²¹ is independently —OCHBr₂. Inembodiments, R²¹ is independently —OCHI₂. In embodiments, R²¹ isindependently —OCHF₂. In embodiments, R²¹ is independently —OCH₂Cl. Inembodiments, R²¹ is independently —OCH₂Br. In embodiments, R²¹ isindependently —OCH₂I. In embodiments, R²¹ is independently —OCH₂F. Inembodiments, R²¹ is independently —N₃.

In embodiments, R²¹ is R²²-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²¹ isR²²-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²¹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R²¹ is R²²-substituted methyl.In embodiments, R²¹ is R²²-substituted ethyl. In embodiments, R²¹ isR²²-substituted propyl. In embodiments, R²¹ is R²²-substituted butyl. Inembodiments, R²¹ is R²²-substituted t-butyl. In embodiments, R²¹ isR²²-substituted pentyl. In embodiments, R²¹ is unsubstituted methyl. Inembodiments, R²¹ is unsubstituted ethyl. In embodiments, R²¹ isunsubstituted propyl. In embodiments, R²¹ is unsubstituted butyl. Inembodiments, R²¹ is unsubstituted t-butyl. In embodiments, R²¹ isunsubstituted pentyl.

In embodiments, R²¹ is R²²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²¹ is R²²-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²¹ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted cycloalkyl(e.g., C3⁻Cs cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²¹ is R²²-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²¹ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²¹ is R²²-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²¹ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²¹ isR²²-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²¹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²¹ is R²²-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²¹ is R²²-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²¹ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, twoadjacent R²¹ substituents are joined to form an R²²-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R²²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²²-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, two adjacent R²¹ substituents are joined to form anR²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, two adjacent R²¹substituents are joined to form an R²²-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, two adjacent R²¹ substituents are joined to form anR²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, two adjacent R²¹ substituents are joined toform an R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R²¹A, R^(21B), R^(21C), and R^(21D) are independentlyhydrogen, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂,—CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂,—OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂R²²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), R²²-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R²²-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R²²-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²²-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(21A) and R^(21B) substituents bonded to the samenitrogen atom are joined to form an R²²-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(21A) and R^(21B) substituents bonded to the samenitrogen atom are joined to form an R²²-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl. In embodiments, R^(21A) and R^(21B)substituents bonded to the same nitrogen atom are joined to form anR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R²² is independently oxo, halogen, 13 CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, -NHNH₂, -ONH₂,-NHC(O)NHNH₂, -NHC(O)NH₂, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCL₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R²³-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²³-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²³-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²³-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²² is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²²is independently —OH. In embodiments, R²² is independently —OCH₃. Inembodiments, R²² is independently —OCH₂CH₃. In embodiments, R²² isindependently —F. In embodiments, R²² is independently —NHC(O)CH₃. Inembodiments, R²² is independently —COOH. In embodiments, R²² isindependently —SO₂NH₂.

In embodiments, R²³ is independently oxo. In embodiments, R²³ isindependently halogen. In embodiments, R²³ is independently —F. Inembodiments, R²³ is independently —Cl. In embodiments, R²³ isindependently —Br. In embodiments, R²³ is independently —I. Inembodiments, R²³ is independently —CCl₃. In embodiments, R²³ isindependently —CBr₃. In embodiments, R²³ is independently —CF₃. Inembodiments, R²³ is independently —CI₃. In embodiments, R²³ isindependently CHCl₂. In embodiments, R²³ is independently —CHBr₂. Inembodiments, R²³ is independently —CHF₂. In embodiments, R²³ isindependently —CHI₂. In embodiments, R²³ is independently —CH₂Cl Inembodiments, R²³ is independently —CH₂Br. In embodiments, R²³ isindependently —CH₂F. In embodiments, R²³ is independently —CH₂I. Inembodiments, R²³ is independently —CN. In embodiments, R²³ isindependently —OH. In embodiments, R²³ is independently —NH₂. Inembodiments, R²³ is independently —COOH. In embodiments, R²³ isindependently —CONH₂. In embodiments, R²³ is independently —NO₂. Inembodiments, R²³ is independently —SH. In embodiments, R²³ isindependently —SO₃H. In embodiments, R²³ is independently —SO₄H. Inembodiments, R²³ is independently —SO₂NH₂.

In embodiments, R²³ is independently NHNH₂. In embodiments, R²³ isindependently —ONH₂. In embodiments, R²³ is independently —NHC(O)NHNH₂.In embodiments, R²³ is independently —NHC(O)NH₂. In embodiments, R²³ isindependently —NHSO₂H. In embodiments, R²³ is independently —NHC(O)H. Inembodiments, R²³ is independently —NHC(O)OH. In embodiments, R²³ isindependently —NHOH. In embodiments, R²³ is independently —OCCl₃. Inembodiments, R²³ is independently —OCF₃. In embodiments, R²³ isindependently —OCBr₃. In embodiments, R²³ is independently —OCI₃. Inembodiments, R²³ is independently —OCHCl₂. In embodiments, R²³ isindependently —OCHBr₂. In embodiments, R²³ is independently —OCHI₂. Inembodiments, R²³ is independently —OCHF₂. In embodiments, R²³ isindependently —OCH₂Cl In embodiments, R²³ is independently —OCH₂Br. Inembodiments, R²³ is independently —OCH2I. In embodiments, R²³ isindependently —OCH₂F. In embodiments, R²³ is independently —N₃.

In embodiments, R²³ is independently halogen. In embodiments, R²³ isindependently —CX²³ ₃. In embodiments, R²³ is independently —CHX²³ ₂. Inembodiments, R²³ is independently —CH₂X²³. In embodiments, R²³ isindependently —OCX²³ ₃. In embodiments, R²³ is independently —OCH₂X²³.In embodiments, R²³ is independently —OCHX²³ ₂. In embodiments, R²³ isindependently —CN. In embodiments, R²³ is independently —SO_(n23)H. Inembodiments, R²³ is independently —SH. In embodiments, R²³ isindependently —SO₂H. In embodiments, R²³ is independently —SO_(v23)NH₂.In embodiments, R²³ is independently —SO₂NH₂. In embodiments, R²³ isindependently —NHC(O)NH₂. In embodiments, R²³ is independently—N(O)_(m23.) In embodiments, R²³ is independently —NH². In embodiments,R²³ is independently —C(O)H. In embodiments, R²³ is independently—C(O)—OH. In embodiments, R²³ is independently —C(O)NH₂. In embodiments,R²³ is independently —OH.

In embodiments, R²³ is independently —NHSO₂H. In embodiments, R²³ isindependently NHC(O)H. In embodiments, R²³ is independently —NHC(O)OH.In embodiments, R²³ is independently —NHOH. In embodiments, R²³ isindependently methoxy. In embodiments, R²³ is independently ethoxy. Inembodiments, R²³ is independently propoxy. In embodiments, R²³ isindependently butoxy. In embodiments, R²³ is independently pentoxy. X²³is —F, —Cl, —Br, and —I.

In embodiments, R²³ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²² is independently oxo. In embodiments, R²² isindependently halogen. In embodiments, R²² is independently —F. Inembodiments, R²² is independently —Cl. In embodiments, R²² isindependently —Br. In embodiments, R²² is independently —I. Inembodiments, R²² is independently —CCl₃. In embodiments, R²² isindependently —CBr₃. In embodiments, R²² is independently —CF₃. Inembodiments, R²² is independently —CI₃. In embodiments, R²² isindependently CHCl₂. In embodiments, R²² is independently —CHBr₂. Inembodiments, R²² is independently —CHF₂. In embodiments, R²² isindependently —CHI₂. In embodiments, R²² is independently —CH₂Cl Inembodiments, R²² is independently —CH₂Br. In embodiments, R²² isindependently —CH₂F. In embodiments, R²² is independently —CH₂I. Inembodiments, R²² is independently —CN. In embodiments, R²² isindependently —OH. In embodiments, R²² is independently —NH₂. Inembodiments, R²² is independently —COOH. In embodiments, R²² isindependently —CONH₂. In embodiments, R²² is independently —NO₂. Inembodiments, R²² is independently —SH. In embodiments, R²² isindependently —SO₃H. In embodiments, R²² is independently —SO₄ H. Inembodiments, R²² is independently —SO₂NH₂. In embodiments, R²² isindependently —NHNH₂. In embodiments, R²² is independently —ONH₂. Inembodiments, R²² is independently —NHC(O)NHNH₂. In embodiments, R²² isindependently —NHC(O)NH₂. In embodiments, R²² is independently —NHSO₂H.In embodiments, R²² is independently —NHC(O)H. In embodiments, R²² isindependently —NHC(O)OH. In embodiments, R²² is independently —NHOH. Inembodiments, R²² is independently —OCCl₃. In embodiments, R²² isindependently —OCF₃. In embodiments, R²² is independently —OCBr₃. Inembodiments, R²² is independently —OCI₃. In embodiments, R²² isindependently —OCHCl₂. In embodiments, R²² is independently —OCHBr₂. Inembodiments, R²² is independently —OCHI₂. In embodiments, R²² isindependently —OCHF₂. In embodiments, R²² is independently —OCH₂Cl Inembodiments, R²² is independently —OCH₂Br. In embodiments, R²² isindependently —OCH₂I. In embodiments, R²² is independently —OCH₂F. Inembodiments, R²² is independently —N₃.

In embodiments, R²² is independently halogen. In embodiments, R²² isindependently —CX²² ₃. In embodiments, R²² is independently —CHX²² ₂. Inembodiments, R²² is independently —CH₂X²²s In embodiments, R²² isindependently —OCX²² ₃. In embodiments, R²² is independently —OCH₂X²².In embodiments, R²² is independently —OCHX²² ₂. In embodiments, R²² isindependently —CN. In embodiments, R²² is independently —SO₂H. Inembodiments, R²² is independently —SH. In embodiments, R²² isindependently —SO₂H. In embodiments, R²² is independently —SO₂NH₂R²². Inembodiments, R²² is independently SO₂NH₂. In embodiments, R²² isindependently —NHC(O)NH₂. In embodiments, R²² is independently —N(O)2.In embodiments, R²² is independently —NH₂. In embodiments, R²² isindependently —C(O)R²². In embodiments, R²² is independently —C(O)—OH.In embodiments, R²² is independently —C(O)NH₂. In embodiments, R²² isindependently —OH. In embodiments, R²² is independently —NHSO₂H. Inembodiments, R²² is independently —NHC(O) H. In embodiments, R²² isindependently —NHC(O)OH. In embodiments, R²² is independently —NHOH. Inembodiments, R²² is independently methoxy. In embodiments, R²² isindependently ethoxy. In embodiments, R²² is independently propoxy. Inembodiments, R²² is independently butoxy. In embodiments, R²² isindependently pentoxy. X²² is —F, —Cl, —Br, and —I.

In embodiments, R⁷ is R²¹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ isR²¹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁷ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments,R⁷ is R²¹-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R⁷ is an unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁷ is R²¹-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁷ is R²¹-substituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁷ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁷ isR²¹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁷ is R²¹-substitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R⁷ is an unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁷ is R²¹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁷ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R⁷ is R²¹-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁷is R²¹-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁷is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R⁷ is hydrogen.

In embodiments, R^(7A), R^(7B), R^(7C), and R^(7D) are independentlyhydrogen, halogen, —CF₃, —CBr₃, —CCl₃, —Cl₃—CHF₂, —CHBr₂,—CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃, —OCBr₃, —OCCl₃,—OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OC H₂Br, —OCH₂Cl,—OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R²¹-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²¹-substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²¹-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²¹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²¹-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(7A) and R^(7B) substituents bonded to the samenitrogen atom are joined to form an R²¹-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orR²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(7A) and R^(7B) substituents bonded to the samenitrogen atom are joined to form an R²¹-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl. In embodiments, R^(7A) and R^(7B)substituents bonded to the same nitrogen atom are joined to form anR²¹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²¹ is independently halogen, —CX²¹ ₃, —CHX²¹ ₂,—CH₂X²¹, —OCX²¹ ₃, —OCH₂X²¹, —OCHX²¹ ₂, —CN, —SO_(n21)R^(21D),—SO_(v21)NR^(21A)R^(21B), —NHC(O)NR^(21A)R^(b 21B), —N(O)_(m21), —NR^(21A)R_(21B), —C(O)R_(21C), —C(O)—OR^(21C), —C(O)NR^(21A)R^(21B),—OR^(21D), —NR^(21A)SO₂R_(21D), —NR^(21 A)C(O)R^(21C),—NR^(21A)C(O)OR^(21C), —NR^(21A)OR^(21C), R²²-substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²²-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R²¹ is halogen,—CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹,—OCX²¹ ₃, —OCH₂X²¹, —OCHX²¹ ₂, —CN, —SO_(n21)R^(21D),—SO_(v21)NR^(21A)R^(21B), —NHC(O)NR^(21A)R^(b 21B), —N(O)_(m21), —NR^(21A)R_(21B), —C(O)R_(21C), —C(O)—OR^(21C), —C(O)NR^(21A)R^(21B),—OR^(21D), —NR^(21A)SO₂R_(21D), —NR^(21 A)C(O)R^(21C),—NR^(21A)C(O)OR^(21C), —NR^(21A)OR^(21C), unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X²¹ isindependently halogen. In embodiments, X²¹ is independently —F. Inembodiments, X²¹ is independently —Cl. In embodiments, X²¹ isindependently —Br.

In embodiments, X²¹ is independently —I.

In embodiments, R²¹ is independently halogen. In embodiments, R²¹ isindependently —CX²¹3. In embodiments, R²¹ is independently —CHX²¹2. Inembodiments, R²¹ is independently —CH₂X²¹. In embodiments, R²¹ isindependently —OCX²¹3. In embodiments, R²¹ is independently —OCH2X²¹. Inembodiments, R²¹ is independently —OCHX²¹ ₂. In embodiments, R²¹ isindependently —CN. In embodiments, R²¹ is independently —SO_(n21)R^(21D)In embodiments, R²¹ is independently In embodiments, R²¹ isindependently —SO₂R^(21D). In embodiments, R²¹ is independently—SO_(v21)NR^(21A)R^(21B). In embodiments, R²¹ is independently—SO₂NR^(21A)R^(21B). In embodiments, R²¹ is independently—NHC(O)NR^(21A)R^(21B). In embodiments, R²¹ is independently —N(O)m2t.In embodiments, R²¹ is independently —NR^(21A)R^(21B). In embodiments,R21 is independently —C(O)R^(21c). In embodiments, R²¹ is independently—C(O)—OR^(21c). In embodiments, R²¹ is independently—C(O)^(NR21A)R^(21B). In embodiments, R21 is independently —OR'. Inembodiments, R²¹ is independently —NR^(21A)SO₂R^(21C). In embodiments,R²¹ is independently —NR^(21A)C(O)R^(21C). In embodiments, R²¹ isindependently —NR^(21A)C(O)0R^(21c). In embodiments, R²¹ isindependently —NR^(21A)SO₂R^(21D). In embodiments, R²¹ is independentlymethoxy. In embodiments, R²¹ is independently ethoxy. In embodiments,R²¹ is independently propoxy. In embodiments, R²¹ is independentlybutoxy. In embodiments, R²¹ is independently pentoxy.

In embodiments, R^(21A) is independently hydrogen. In embodiments,R^(21A) is independently —CF₃. In embodiments, R^(21A) is independently—CBr₃. In embodiments, R^(21A) is independently —CC₁₃. In embodiments,R^(21A) is independently —CI₃. In embodiments, R^(21A) is independently—CHF₂. In embodiments, R^(21A) is independently —CHBr₂. In embodiments,R_(21A) is independently —CHCl₂. In embodiments, R^(2IA) isindependently —CHI₂. In embodiments, R^(21A) is independently —CH₂F. Inembodiments, R^(21A) is independently —CH₂Br. In embodiments, R^(21A) isindependently —CH₂Cl In embodiments, R^(21A) is independently —CH₂I. Inembodiments, R^(2IA) is independently —OH. In embodiments, R^(21A) isindependently —COOH. In embodiments, R^(21A) is independently —CON₂. Inembodiments, R^(21A) is independently R²²-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(21A) is independently R²²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(21A) is independentlyR²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(21A) isindependently R²²-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(21A) isindependently R²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R^(21A) is independentlyR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(21A) is independently unsubstituted methyl. Inembodiments, R^(21A) is independently unsubstituted ethyl. Inembodiments, R^(21A) is independently unsubstituted propyl. Inembodiments, R^(21A) is independently unsubstituted butyl. Inembodiments, R^(21A) is independently unsubstituted pentyl. Inembodiments, R^(21A) is independently unsubstituted hexyl.

In embodiments, R^(21B) is independently hydrogen. In embodiments, R²¹is independently —CF₃. In embodiments, R²¹ is independently —CBr₃. Inembodiments, R^(21B) is independently —CCl₃. In embodiments, R^(21B) isindependently —CI₃. In embodiments, R^(21B) is independently —CHF₂. Inembodiments, R²¹¹³ is independently —CHBr₂. In embodiments, R^(21B) isindependently —CHCl₂. In embodiments, R²¹ is independently —CHI₂. Inembodiments, R²¹ is independently —CH₂F. In embodiments, R²¹ isindependently —CH₂Br. In embodiments, R^(21B) is independently —CH₂Cl Inembodiments, R^(21B) is independently —CH₂I. In embodiments, R²¹ isindependently —OH. In embodiments, R²¹ is independently —COOH. Inembodiments, R²¹ is independently —CONH₂. In embodiments, R^(21B) isindependently R²²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(21B) is independentlyR²²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R^(21B) is independently R²²-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl). In embodiments, R²¹ is independentlyR²²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R^(21B) is independentlyR²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R²¹ is independently R²²-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²¹is independently unsubstituted methyl. In embodiments, R²¹ isindependently unsubstituted ethyl. In embodiments, R²¹ is independentlyunsubstituted propyl. In embodiments, R^(21B) is independentlyunsubstituted butyl. In embodiments, R^(21B) is independentlyunsubstituted pentyl. In embodiments, R^(21B) is independentlyunsubstituted hexyl.

In embodiments, R^(21c) is independently hydrogen. In embodiments,R^(21c) is independently —CF₃. In embodiments, R^(21c) is independently—CBr₃. In embodiments, R^(21c) is independently —CCl₃. In embodiments,R^(21c) is independently —CI₃. In embodiments, R^(21c) is independently—CHF₂. In embodiments, R^(21c) is independently —CHBr₂. In embodiments,

R^(21c) is independently —CHCl₂. In embodiments, R^(21c) isindependently —CHI₂. In embodiments, R^(21c) is independently —CH₂F. Inembodiments, R^(21c) is independently —CH₂Br. In embodiments, R^(21c) isindependently —CH₂Cl In embodiments, R^(21c) is independently —CH₂I. Inembodiments, R^(21c) is independently —OH. In embodiments, R^(21c) isindependently —COOH. In embodiments, R^(21c) is independently —CONH₂. Inembodiments, R^(21c) is independently R²²-substituted or unsubstitutedalkyl (e.g., C₁-Cg alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). hi embodiments,R^(21c) is independently R²²-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(21c) is independentlyR²²-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(21c) isindependently R²²-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(21c) isindependently R²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R^(21c) is independentlyR²²-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(21c) is independently unsubstituted methyl. Inembodiments, R^(21c) is independently unsubstituted ethyl. Inembodiments, R^(21c) is independently unsubstituted propyl. Inembodiments, R^(21c) is independently unsubstituted butyl. Inembodiments, R^(21c) is independently unsubstituted pentyl. Inembodiments, R^(21c) is independently unsubstituted hexyl.

In embodiments, R^(21D) is independently hydrogen. In embodiments,R^(21D) is independently —CF₃. In embodiments, R^(21D) is independently—CBr₃. In embodiments, R^(21D) is independently —CCl₃. In embodiments,R^(21D) is independently —CI₃. In embodiments, R^(21D) is independently—CHF₂. In embodiments, R^(21D) is independently —CHBr₂. In embodiments,R²¹ is independently —CHCl₂. In embodiments, R²¹ is independently —CHI₂.In embodiments, R^(21D) is independently —CH₂F. In embodiments, R^(21D)is independently —CH₂Br. In embodiments, R^(21D) is independently —CH₂ClIn embodiments, R^(21D) is independently —CH₂I. In embodiments, R²¹ isindependently —OH. In embodiments, R²¹ is independently —COOH. Inembodiments, R²¹ is independently —CONH₂. In embodiments, R²¹ isindependently R²²-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R^(21D) is independentlyR²²-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). hi embodiments, R^(21D) is independently R²²-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl). In embodiments, R^(21D) is independentlyR²²-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R ^(21D) is independentlyR²²-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R ^(21D) is independently R²²-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R^(21D) is independently unsubstituted methyl. In embodiments, R^(21D)is independently unsubstituted ethyl. In embodiments, R^(21D) isindependently unsubstituted propyl. In embodiments, R^(21D) isindependently unsubstituted butyl. In embodiments, R^(21D) isindependently unsubstituted pentyl. In embodiments, R^(21D) isindependently unsubstituted hexyl.

In embodiments, R¹ is substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁸ is substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R⁸ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄alkyl).

In embodiments, R⁸ is R²⁴-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁸ isR²⁴-substituted alkyl (e.g. C₁-Cs alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁸ is an unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, R⁸ is hydrogen. In embodiments,R⁸ is unsubstituted methyl. In embodiments, R⁸ is unsubstituted ethyl.In embodiments, R⁸ is unsubstituted propyl.

R²⁴ is independently halogen, —CX²⁴ ₃, —CHX²⁴ ₂, —CH₂X²⁴, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX²⁴₃, —OCHX²⁴ ₂, —OCH₂X²⁴, unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X²⁴ is —F, —Cl,—Br, and —I.

In embodiments, R⁹ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R⁹ is independently —F. In embodiments, R⁹is independently —Cl. In embodiments, R⁹ is independently —Br. Inembodiments, R⁹ is independently —I.

In embodiments, R⁹ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R²⁵-substituted orunsubstituted alkyl (e.g., C₁-Cs alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁵-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl),

R²⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R⁹ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is independently oxo. In embodiments, R⁹ isindependently halogen. In embodiments, R⁹ is independently —CCl₃. Inembodiments, R⁹ is independently —CBr₃. In embodiments, R⁹ isindependently —CF₃. In embodiments, R⁹ is independently —CI₃. Inembodiments, R⁹ is independently CHCl₂. In embodiments, R⁹ isindependently —CHBr₂. In embodiments, R⁹ is independently —CHF₂. Inembodiments, R⁹ is independently —CHI₂. In embodiments, R⁹ isindependently —CH₂Cl In embodiments, R⁹ is independently —CH₂Br. Inembodiments, R⁹ is independently —CH ₂F. In embodiments, R⁹ isindependently —CH₂I. In embodiments, R⁹ is independently —CN. Inembodiments, R⁹ is independently —OH. In embodiments, R⁹ isindependently —NH₂. In embodiments, R⁹ is independently —COOH. Inembodiments, R⁹ is independently —CONH₂. In embodiments, R⁹ isindependently —NO₂. In embodiments, R⁹ is independently —SH. Inembodiments, R⁹ is independently —SO₃H. In embodiments, R⁹ isindependently —SO₄H. In embodiments, R⁹ is independently —SO₂NH₂. Inembodiments, R⁹ is independently —NHNH₂. In embodiments, R⁹ isindependently —ONH₂. In embodiments, R⁹ is independently —NHC(O)NHNH₂.In embodiments, R⁹ is independently —NHC(O)NH₂. In embodiments, R⁹ isindependently —NHSO₂H. In embodiments, R⁹ is independently —NHC(O)H. Inembodiments, R⁹ is independently —NHC(O)OH. In embodiments, R⁹ isindependently —NHOH. In embodiments, R⁹ is independently —OCCl₃. Inembodiments, R⁹ is independently —OCF₃. In embodiments, R⁹ isindependently —OCBr₃. In embodiments, R⁹ is independently —OCI₃. Inembodiments, R⁹ is independently —OCHCl₂. In embodiments, R⁹ isindependently —OCHBr₂. In embodiments, R⁹ is independently —OCHI₂. Inembodiments, R⁹ is independently -—OCHF₂. In embodiments, R⁹ isindependently —OCH₂Cl In embodiments, R⁹ is independently —OCH₂Br. Inembodiments, R⁹ is independently —OCH₂I. In embodiments, R⁹ isindependently —OCH₂F. In embodiments, R⁹ is independently —N₃.

In embodiments, R⁹ is R²⁵-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁹ isR²⁵-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁹ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or CI-CI alkyl). In embodiments, R⁹ is R²⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments,R⁹ is R²⁵-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R⁹ is an unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R⁹ is R²⁵-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R⁹ is R²⁵-substituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁹ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁹ isR²⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁹ is R²⁵-substitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R⁹ is an unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R⁹ is R²⁵-substituted orunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R⁹ is R²⁵-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, R⁹ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R⁹ is R²⁵-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁹is R²⁵-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R⁹is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,two adjacent R⁹ substituents are joined to form an R²⁵-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R²⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, two adjacent R⁹ substituents are joined to form anR²⁵-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, two adjacent R⁹substituents are joined to form an R²⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, two adjacent R⁹ substituents are joined to form anR²⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, two adjacent R⁹ substituents are joined to forman R²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, -SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R²⁶-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁶-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁶-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁶-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁶-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²⁵ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁵ is independently oxo. In embodiments, R²⁵ isindependently halogen. In embodiments, R²⁵ is independently —CCl₃. Inembodiments, R²⁵ is independently —CBr₃. In embodiments, R²⁵ isindependently —CF₃. In embodiments, R²⁵ is independently —CI₃. Inembodiments, R²⁵ is independently CHCl₂. In embodiments, R²⁵ isindependently —CHBr₂. In embodiments, R²⁵ is independently —CHF₂. Inembodiments, R²⁵ is independently —CHI₂. In embodiments, R²⁵ isindependently —CH₂Cl In embodiments, R²⁵ is independently —CH₂Br. Inembodiments, R²⁵ is independently —CH₂F. In embodiments, R²⁵ isindependently —CH₂I. In embodiments, R²⁵ is independently —CN. Inembodiments, R²⁵ is independently —OH. In embodiments, R²⁵ isindependently —NH₂. In embodiments, R²⁵ is independently —COOH. Inembodiments, R²⁵ is independently —CONH₂. In embodiments, R²⁵ isindependently —NO₂. In embodiments, R²⁵ is independently —SH. Inembodiments, R²⁵ is independently —SO₃H. In embodiments, R²⁵ isindependently —SO₄H. In embodiments, R²⁵ is independently —SO₂NH₂. Inembodiments, R²⁵ is independently —NHNH₂. In embodiments, R²⁵ isindependently —ONH₂. In embodiments, R²⁵ is independently —NHC(O)NHNH₂.In embodiments, R²⁵ is independently —NHC(O)NH₂. In embodiments, R²⁵ isindependently —HNSO₂H. In embodiments, R²⁵ is independently —NHC(O)H. Inembodiments, R²⁵ is independently —NHC(O)0H. In embodiments, R²⁵ isindependently —NHOH. In embodiments, R²⁵ is independently —OCCl₃. Inembodiments, R²⁵ is independently —OCF₃. In embodiments, R²⁵ isindependently —OCBr₃. In embodiments, R²⁵ is independently OCI₃. Inembodiments, R²⁵ is independently —OCHCl₂. In embodiments, R²⁵ isindependently —OCHBr₂. In embodiments, R²⁵ is independently —OCHI₂. Inembodiments, R²⁵ is independently —OCHF₂. In embodiments, R²⁵ isindependently —OCH₂Cl In embodiments, R²⁵ is independently —OCH₂Br. Inembodiments, R²⁵ is independently —OCH2I. In embodiments, R²⁵ isindependently —OCH₂F. In embodiments, R²⁵ is independently —N₃.

In embodiments, R²⁵ is R²⁶-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁵ isR²⁶-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl,

C₁-C₆ alkyl, or C₁-C₄ alkyl)

In embodiments, R²⁵ is R²⁶-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁵ is R²⁶-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁵ is R²⁶-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁵ is R²⁶-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁵ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁵ is R²⁶-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁵ is R²⁶-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁵ is R²⁶-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁵ isR²⁶-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁵ is R²⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁵ is R²⁶-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁵ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, -SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R²⁶-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁷-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁷-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁷-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁷-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁷-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²⁶ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁶is independently —OH. In embodiments, R²⁶ is independently —OCH₃. Inembodiments, R²⁶ is independently —OCH₂CH₃. In embodiments, R²⁶ isindependently —F. In embodiments, R²⁶ is independently —NHC(O)CH3. Inembodiments, R²⁶ is independently —COOH. In embodiments, R²⁶ isindependently —SO₂NH₂.

In embodiments, R²⁷ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(9A), R^(9B), R^(9C), and R^(9D) are independentlyhydrogen, halogen,—CF₃, —CBr₃, —CCl₃, —Cl₃—CHF₂, —CHBr₂,—CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃, —OCBr₃, —OCCl₃,—OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OC H₂Br, —OCH₂Cl,—OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R²⁵-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁵-substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁵-substitutedor unsubstituted cycloalkyl (e.g., C3⁻C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(9A) and R^(9B) substituents bonded to the samenitrogen atom are joined to form an R²⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orR²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(9A) and R^(9B) substituents bonded to the samenitrogen atom are joined to form an R²⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl. In embodiments, R^(9A) and R^(9B)substituents bonded to the same nitrogen atom are joined to form anR²⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁰ is independently —F. In embodiments,R¹⁰ is independently —Cl. In embodiments, R^(m) is independently —Br. Inembodiments, R¹⁰ is independently —I.

In embodiments, R¹⁰ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R²⁸-substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁸-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁰ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ s R²⁸-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R¹⁰ isR²⁸-substituted alkyl (e.g C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). Inembodiments, R¹⁰ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl). In embodiments, It^(l)° is R²⁸-substituted orunsubstituted heteroalkyl (e.g 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments,R¹⁰ is R²⁸-substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). Inembodiments, R¹⁰ is an unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl). In embodiments, R¹⁰ is R²⁸-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl). In embodiments, R¹⁰ is R²⁸-substituted cycloalkyl (e.g.,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R¹⁰ is an unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R¹⁰ isR²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R¹⁰ is R²⁸-substitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl). Inembodiments, R¹⁰ is an unsubstituted heterocycloalkyl (e.g., 3 to 8membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl). In embodiments, R¹⁰ is R²⁸-substituted orunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R¹⁰ is R²⁸-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl). In embodiments, R¹⁰ is an unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl). In embodiments, R¹⁰ is R²⁸-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁰is R²⁸-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,R¹⁰is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments,two adjacentR¹⁰ substituents are joined to form an R²⁸-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl), R²⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁸-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, two adjacent R^(m) substituents are joined to form anR²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, two adjacentR^(m) substituents are joined to form an R²⁸-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).In embodiments, two adjacentR¹⁰ substituents are joined to form anR²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl). In embodiments, two adjacent R¹⁰ substituents are joined toform an R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁰ is independently oxo. In embodiments, R¹⁰ isindependently halogen. In embodiments, R¹⁰ is independently —CCl₃. Inembodiments, R¹ is independently —CBr₃. In embodiments, R¹⁰ isindependently —CF₃. In embodiments, R¹⁰ is independently —CI₃. Inembodiments, R¹⁰ is independently CHCl₂. In embodiments, R¹⁰ isindependently —CHBr₂. In embodiments, R¹⁰ is independently —CHF₂. Inembodiments, R¹⁰ is independently —CHI₂. In embodiments, R¹⁰ isindependently —CH₂Cl In embodiments, R¹⁰ is independently —CH₂Br. Inembodiments, R¹⁰ is independently —CH₂F. In embodiments, R¹⁰ isindependently —CH₂I. In embodiments, R¹⁰ is independently —CN. Inembodiments, R¹⁰ is independently —OH. In embodiments, R¹⁰ isindependently —NH₂. In embodiments, R¹⁰ is independently —COOH. Inembodiments, R¹⁰ is independently —CONH₂. In embodiments, R¹⁰ isindependently —NO₂. In embodiments, R¹ is independently —SH. Inembodiments, R¹⁰ is independently —SO₃H. In embodiments, R¹⁰ isindependently —SO₄H. In embodiments, R¹⁰ is independently —SO₂NH₂. Inembodiments, R¹⁰ is independently —NHNH₂. In embodiments, R¹⁰ isindependently —ONH₂. In embodiments, R¹⁰ is independently —NHC(O)NHNH₂.In embodiments, R¹⁰ is independently —NHC(O)NH₂. In embodiments, R¹⁰ isindependently —HNSO₂H. In embodiments, R¹⁰ is independently —NHC(O)H. Inembodiments, R¹⁰ is independently —NHC(O)OH. In embodiments, R¹⁰ isindependently —NHOH. In embodiments, R¹⁰ is independently —OCCl₃. Inembodiments, R¹⁰ is independently —OCF₃. In embodiments, R¹⁰ isindependently —OCBr₃. In embodiments, R¹⁰ is independently OCI₃. Inembodiments, R¹⁰ is independently —OCHCl₂. In embodiments, R¹⁰ isindependently —OCHBr₂. In embodiments, R¹⁰ is independently —OCHI₂. Inembodiments, R¹⁰ is independently —OCHF₂. In embodiments, R¹⁰ isindependently —OCH₂Cl.

In embodiments, R¹⁰ is independently —OCH₂Br. In embodiments, R¹⁰ isindependently —OCH₂I. In embodiments, R¹⁰ is independently —OCH₂F. Inembodiments, R¹⁰ is independently —N₃.

R²⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, -SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R²⁶-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁹-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁹-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁹-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²⁸ is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C1-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁸ is independently oxo. In embodiments, R²⁸ isindependently halogen. In embodiments, R²⁸ is independently —CCl₃. Inembodiments, R²⁸ is independently —CBr₃. In embodiments, R²⁸ isindependently —CF₃. In embodiments, R²⁸ is independently —CI₃. Inembodiments, R²⁸ is independently CHCl₂. In embodiments, R²⁸ isindependently —CHBr₂. In embodiments, R²⁸ is independently —CHF₂. Inembodiments, R²⁸ is independently —CHI₂. In embodiments, R²⁸ isindependently —CH₂Cl In embodiments, R²⁸ is independently —CH₂Br. Inembodiments, R²⁸ is independently —CH₂F. In embodiments, R²⁸ isindependently —CH₂I. In embodiments, R²⁸ is independently —CN. Inembodiments, R²⁸ is independently —OH. In embodiments, R²⁸ isindependently —NH₂. In embodiments, R²⁸ is independently —COOH. Inembodiments, R²⁸ is independently —CONH₂. In embodiments, R²⁸ isindependently —NO₂. In embodiments, R²⁸ is independently —SH. Inembodiments, R²⁸ is independently —SO₃H. In embodiments, R²⁸ isindependently —SO₄H. In embodiments, R²⁸ is independently —SO₂NH₂. Inembodiments, R²⁸ is independently —NHNH₂. In embodiments, R²⁸ isindependently —ONH₂. In em bodiments, R²⁸ is independently —NHC(O)NHNH₂.In embodiments, R²⁸ is independently NHC(O)NH₂. In embodiments, R²⁸ isindependently —HNSO₂H. In embodiments, R²⁸ is independently —NHC(O)H. Inembodiments, R²⁸ is independently —NHC(O)OH. In embodiments, R²⁸ isindependently —NHOH. In embodiments, R²⁸ is independently —OCCl₃. Inembodiments, R²⁸ is independently —OCF₃. In embodiments, R²⁸ isindependently —OCBr₃. In embodiments, R²⁸ is independently OCI₃. Inembodiments, R²⁸ is independently —OCHCl₂. In embodiments, R²⁸ isindependently —OCHBr₂. In embodiments, R²⁸ is independently —OCHI₂. Inembodiments, R²⁸ is independently —OCHF₂. In embodiments, R²⁸ isindependently —OCH₂Cl. In embodiments, R²⁸ is independently —OCH₂Br. Inembodiments, R²⁸ is independently —OCH2I. In embodiments, R²⁸ isindependently —OCH₂F. In embodiments, R²⁸ is independently —N₃.

In embodiments, R²⁸ is R²⁹-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R²⁸ isR²⁹-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R²⁸ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl)

In embodiments, R²⁸ is R²⁹-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R²⁸ is R²⁹-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R²⁸ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R²⁸ is R²⁹-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R²⁸ is R²⁹-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R²⁸ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R²⁸ is R²⁹-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R²⁸ is R²⁹-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R²⁸ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R²⁸ is R²⁹-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R²⁸ isR²⁹-substituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). Inembodiments, R²⁸ is an unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl,or phenyl).

In embodiments, R²⁸ is R²⁹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R²⁸ is R²⁹-substitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁸ is anunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, -SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R^(N)-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁰-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R^(N)-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R^(N)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(N)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R^(N)-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R²⁹ is independently oxo, halogen, —CF₃,—CBr₃, —CCl₃, —CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂,—OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²⁹is independently —OH. In embodiments, R²⁹ is independently —OCH₃. Inembodiments, R²⁹ is independently —OCH₂CH₃. In embodiments, R²⁹ isindependently —F. In embodiments, R²⁹ is independently —NHC(O)CH₃. Inembodiments, R²⁹ is independently —COOH. In embodiments, R²⁹ isindependently —SO₂NH₂.

In embodiments, R³° is independently oxo, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃,—OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OCH₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, unsubstituted alkyl (e.g.,C1-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(10A) , R^(10B), R^(10C), and R^(10D) areindependently hydrogen, halogen, —CF₃, —CBr₃, —CCl₃, —Cl₃—CHF₂, —CHBr₂,—CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OCF₃, —OCBr₃, —OCCl₃,—OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂, —OCH₂F, —OC H₂Br, —OCH₂Cl,—OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, R²⁸-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁸-substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁸-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R²⁸-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(10A) and R^(10B) substituents bonded to the samenitrogen atom are joined to form an R²⁸-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl) orR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(10A) and R^(10B) substituents bonded to the samenitrogen atom are joined to form an R²⁸-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl. In embodiments, R^(10A) and R^(10B)substituents bonded to the same nitrogen atom are joined to form anR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is independently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂,—CH₂X¹⁰, —OCX¹⁰ ₃, —OCH₂X¹⁰, —OCHX¹⁰ ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), R²⁸-substituted orunsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁸-substituted or uhsubstituted alkyl (e.g., 2to 8membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),R²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁸-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R¹⁰ is halogen —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰,—OCX¹⁰ ₃, —OCH₂X¹⁰, —OCHX¹⁰ ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or

C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). X¹⁰ is independently halogen. In embodiments, X¹⁰ isindependently —F. In embodiments, X¹⁰ is independently —Cl. Inembodiments, X¹⁰ is independently —Br. In embodiments, X¹⁰ isindependently —I.

In embodiments, R¹⁰ is independently halogen. In embodiments, R¹⁰ isindependently —CX¹⁰ ₃. In embodiments, R¹⁰ is independently —CHX¹⁰ ₂. Inembodiments, R¹⁰ is independently —CH₂X¹⁰ . In embodiments, R¹ isindependently —OCX¹⁰ ₃. In embodiments, R¹⁰ is independently —OCH₂X¹⁰.In embodiments, R¹⁰ is independently —OCHX¹⁰ 2. In embodiments, R¹⁰isindependently —CN. In embodiments, R¹⁰is independently —SO_(n10)R^(10D).

In embodiments, R¹⁰is independently —SR^(10D). In embodiments, R¹⁰isindependently —SO₂R^(10D). In embodiments, R¹⁰is independently—SO_(v10)NR^(10A)R^(10 B). In embodiments, R¹⁰ is independently—SO₂NR^(10A)R^(10B). In embodiments, R¹⁰is independently—NHC(O)NR^(10A)R^(10B). In embodiments, R¹⁰is independently —N(O)_(10m).In embodiments, R¹⁰is independently —NR^(10A)R^(10B). In embodiments,R¹⁰is independently —C(O)R^(10C). In embodiments, R¹⁰is independently—C(O)—OR^(10C). In embodiments, R¹⁰is independently—C(O)NR^(10A)R^(10B). In embodiments, R¹⁰is independently —OR^(10D). Inembodiments, R¹⁰is independently —C(O)—OR^(10A)R^(10B). In embodiments,R¹⁰is independently —NR^(10A)C(O)R^(10C). In embodiments, R¹⁰ isindependently —NR^(10A)C(O)OR^(10C) . In embodiments, R¹⁰isindependently —NR^(10A)OR^(10C). In embodiments, R¹⁰is independentlymethoxy. In embodiments, R¹⁰ is independently ethoxy. In embodiments,R¹⁰is independently propoxy. In embodiments, R¹⁰is independently butoxy.In embodiments, R¹⁰ is independently pentoxy.

In embodiments, R^(10A) is independently hydrogen. In embodiments,R^(10A) is independently —CF₃. In embodiments, R^(10A) is independently—CBr₃. In embodiments, R^(10A) is independently —CCl₃. In embodiments,R^(10A) is independently —CI₃. In embodiments, R^(10A) is independently—CHF₂. In embodiments, R^(10A) is independently —CHBr₂. In embodiments,R^(10A) is independently —CHCl₂. In embodiments, R^(10A) isindependently —CHI₂. In embodiments, R^(10A) is independently —CH₂F. Inembodiments, R^(10A) is independently —CH₂Br. In embodiments, R^(10A) isindependently —CH₂Cl In embodiments, R^(10A) is independently —CH₂I. Inembodiments, R^(10A) is independently —OH. In embodiments, R^(10A) isindependently —COOH. In embodiments, R^(10A) is independently —CONH₂. Inembodiments, R^(10A) is independently R²⁸-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(10A) is independently R²⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(10A) is independentlyR²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(10A) isindependently R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(10A) isindependently R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R^(10A) is independentlyR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(10A) is independently unsubstituted methyl. Inembodiments, R^(10A) is independently unsubstituted ethyl. Inembodiments, R^(10A) is independently unsubstituted propyl. Inembodiments, R^(10A) is independently unsubstituted butyl. Inembodiments, R^(10A) is independently unsubstituted pentyl. Inembodiments, R^(10A) is independently unsubstituted hexyl.

In embodiments, R^(10B) is independently hydrogen. In embodiments,R^(10B) is independently —CF₃. In embodiments, R^(10B) is independently—CBr₃. In embodiments, R^(10B) is independently —CCl₃. In embodiments,R^(10B) is independently —CI₃. In embodiments, R^(10B) is independently—CHF₂. In embodiments, R^(10B) is independently —CHBr₂. In embodiments,R^(10B) is independently —CHCl₂. In embodiments, R^(10B) isindependently —CHI₂. In embodiments, R^(10B) is independently —CH₂F. Inembodiments, R^(10B) is independently —CH₂Br. In embodiments, R^(10B) isindependently —CH₂Cl In embodiments, R^(10B) is independently —CH₂I. Inembodiments, R^(10B) is independently —OH. In embodiments, R^(10B) isindependently —COOH. In embodiments, R^(10B) is independently —CONH₂. Inembodiments, R^(10B) is independently R²⁸-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(10B) is independently R²⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(10B) is independentlyR²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(10B) isindependently R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(10B) isindependently R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R^(10B) is independently10-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(10B) is independently unsubstituted methyl. Inembodiments, R^(10B) is independently unsubstituted ethyl. Inembodiments, R^(10B) is independently unsubstituted propyl. Inembodiments, R^(10B) is independently unsubstituted butyl. Inembodiments, R^(10B) is independently unsubstituted pentyl. Inembodiments, R^(10B) is independently unsubstituted hexyl.

In embodiments, R^(10C) is independently hydrogen. In embodiments,R^(10C) is independently —CF₃. In embodiments, R^(10C) is independently—CBr₃. In embodiments, R^(10C) is independently —CCl₃. In embodiments,R^(10C) is independently —CI₃. In embodiments, R^(10C) is independently—CHF₂. In embodiments, R^(10C) is independently —CHBr₂. In embodiments,R^(10C) is independently —CHCl₂. In embodiments, R^(10C) isindependently —CHI₂. In embodiments, R^(10C) is independently —CH₂F. Inembodiments, R^(10C) is independently —CH₂Br. In embodiments, R^(10C) isindependently —CH₂Cl In embodiments, R^(10C) is independently —CH₂I. Inembodiments, R^(10C) is independently —OH. In embodiments, R^(10C) isindependently —COOH. In embodiments, R^(10C) is independently —CONH₂. Inembodiments, R^(10C) is independently R²⁸-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(10C) is independently R²⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(10C) is independentlyR²⁸-substituted or unsubstituted cycloalkyl (e.g., C3-CS cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(10C) isindependently R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(10C) isindependently R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R^(10C) is independentlyR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(10C) is independently unsubstituted methyl. Inembodiments, R^(10C) is independently unsubstituted ethyl. Inembodiments, R^(10C) is independently unsubstituted propyl. Inembodiments, R^(10C) is independently unsubstituted butyl. Inembodiments, R^(10C) is independently unsubstituted pentyl. Inembodiments, R^(10C) is independently unsubstituted hexyl.

In embodiments, R^(10D) is independently hydrogen. In embodiments,R^(10D) is independently —CF₃. In embodiments, R^(10D) is independently—CBr₃. In embodiments, R^(10D) is independently —CCl₃. In embodiments,R¹⁰ ^(D) is independently —CI₃. In embodiments, R¹⁰ ^(D) isindependently —CHF₂. In embodiments, R¹⁰ ^(D) is independently —CHBr₂.In embodiments, R^(10D) is independently —CHCl₂. In embodiments, R^(ios)is independently —CHI₂. In embodiments, R^(10D) is independently —CH₂F.In embodiments, R^(10D) is independently —CH₂Br. In embodiments, R^(10D)is independently —CH₂Cl In embodiments, R^(10D) is independently —CH₂I.In embodiments, R^(10D) is independently —OH. In embodiments, R^(10D) isindependently —COOH. In embodiments, R^(10D) is independently —CONH₂. Inembodiments, R^(10D) is independently R²⁸-substituted or unsubstitutedalkyl (e.g., C₁-Cg alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments,R^(10D) is independently R²⁸-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R^(10.1) is independentlyR²⁸-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R^(10D) isindependently R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl). In embodiments, R^(ios) isindependently R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl). In embodiments, R^(ios) is independentlyR²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R^(10D) is independently unsubstituted methyl. Inembodiments, R^(10D) is independently unsubstituted ethyl. Inembodiments, R^(10D) is independently unsubstituted propyl. Inembodiments, R^(10D) is independently unsubstituted butyl. Inembodiments, R^(10D) is independently unsubstituted pentyl. Inembodiments, R^(10D) is independently unsubstituted hexyl.

In embodiments, R^(10.1) is independently hydrogen, oxo, halogen, —CF₃,—CBr₃, —CCl₃, —CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂,—OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-Cg alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R^(10.1) is independently hydrogen, halogen, —CX^(10.1)₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —OCX^(10.1) ₃, —OCH₂X^(10.1),—OCHX^(10.1) ₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),R²⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R²⁸-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R²⁸-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(10.1)ishalogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —OCX^(10.1) ₃,—OCH₂X^(10.1), —OCHX^(10.1) ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10),—NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), unsubstituted alkyl (e.g.,C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X^(10.1)′¹ isindependently halogen. In embodiments, X^(10.1) is independently —F. Inembodiments, X^(10.1) is independently —Cl. In embodiments, X^(10.1) isindependently —Br. In embodiments, X^(10.1) is independently —I.

In embodiments, R^(10.1) is independently halogen. In embodiments,R^(10.1) is independently —CX^(10.1) ₃. In embodiments, R^(10.1) isindependently —CHX^(10.1) ₂. In embodiments, R^(10.1) is independently—CH₂X^(10.1). In embodiments, R^(10.1) is independently —OCX^(10.1) ₃.In embodiments, R^(10.1) is independently —OCH₂X^(10.1). In embodiments,R^(10.1) is independently —OCHX^(10.1). In embodiments, R^(10.1) isindependently —CN. In embodiments, R^(10.1) is independently—SO_(n10)R^(10D). In embodiments, R^(10.1) is independently —SR^(10D).In embodiments, R^(10.1) is independently —SO₂R^(10D). In embodiments,R^(10.1) is independently —SO_(v10)NR^(10A)R^(10B). In embodiments,R^(10.1) is independently —SO₂NR^(10A)R^(10B). In embodiments, R^(10.1)is independently —NHC(O)^(10A)R^(10B). In embodiments, R^(10.1) isindependently —N(O)_(m10). In embodiments, R^(10.1) is independently—NR^(10A)R^(10B). In embodiments, R^(10.1) is independently—C(O)R^(10C). In embodiments, R^(10.1) is independently —C(O)—OR^(10C).In embodiments, R^(10.1) is independently —C(O)NR^(10A)R^(10B). Inembodiments, R^(10.1)is independently —OR^(10D). In embodiments,R^(10.1) is independently —NR^(10A)SO₂R^(10D). In embodiments, R^(10.1)is independently —NR^(10A)C(O)R^(10B). In embodiments, R^(10.1) isindependently —NR^(10A)C(O)OR^(10C). In embodiments, R^(10.1) isindependently —NR^(10A)OR^(10C). In embodiments, R^(10.1) isindependently methoxy. In embodiments, R^(10.1) is independently ethoxy.In embodiments, R^(10.1) is independently propoxy. In embodiments,R^(10.1) is independently butoxy. In embodiments, R^(10.1) isindependently pentoxy. In embodiments, R¹⁰ is independently —F. Inembodiments, R¹⁰ is independently —Cl. In embodiments, R^(10.1) isindependently —Br. In embodiments, R^(10.1) is independently —I. Inembodiments, R^(10.1) is independently oxo. In embodiments, R^(10.1) isindependently halogen. In embodiments, R^(10.1) is independently —CCl₃.In embodiments, R^(10.1) is independently —CBr₃. In embodiments,R^(10.1) is independently —CF₃. In embodiments, R^(10.1) isindependently —CI₃. In embodiments, R^(10.1) is independently CHCl₂. Inembodiments, R^(10.1) is independently —CHBr₂. In embodiments, R¹⁰ ¹ isindependently —CHF₂. In embodiments, R^(10.1) is independently —CHI₂. Inembodiments, R^(10.1) is independently —CH₂Cl In embodiments, R^(10.1)is independently —CH₂Br. In embodiments, R¹⁰is independently —CH₂F. Inembodiments, R¹⁰ ¹ is independently —CH₂I. In embodiments, R¹⁰isindependently —CN. In embodiments, R¹⁰ ¹ is independently —OH. Inembodiments, R^(10.1) is independently —NH₂. In embodiments, R^(10.1) isindependently —COOH. In embodiments, R^(10.1) is independently —CONH₂.In embodiments, R^(10.1) is independently —NO₂. In embodiments, R¹⁰isindependently —SH. In embodiments, R^(10.1) is independently —SO₃H. Inembodiments, R¹⁰is independently —SO₄H. In embodiments, R^(10.1) isindependently —SO₂NH₂. In embodiments, R^(10.1) is independently —NHNH₂.In embodiments, R^(10.1) is independently —ONH₂. In embodiments,R^(10.1) is independently —NHC(O)NHNH₂. In embodiments, R^(10.1) isindependently —NHC(O)NH₂. In embodiments, R^(10.1) is independently—HNSO₂H. In embodiments, R^(10.1) is independently —NHC(O)H. Inembodiments, R^(10.1) is independently —NHC(O)OH. In embodiments,R^(10.1) is independently —NHOH. In embodiments, R^(10.1) isindependently —OCCl₃. In embodiments, R^(10.1) is independently —OCF₃.In embodiments, R^(10.1) is independently —OCBr₃. In embodiments,R^(10.1) is independently —OCI₃. In embodiments, R_(10.1) independently—OCHCl₂. In embodiments, R^(10.1) is independently —OCHBr₂. Inembodiments, R^(10.1) is independently —OCHI₂. In embodiments, R^(I)° isindependently —OCHF₂. In embodiments, R^(10. 1) is independently —OCH₂ClIn embodiments, R^(10.1) is independently —OCH₂Br. In embodiments,R^(10.1) is independently —OCH₂I. In embodiments, R^(10.1) independently—OCH₂F. In embodiments, R^(10.1) is independently —N₃. In embodiments,R^(10.1) is independently —CH₃. In embodiments, R^(10.1) isindependently —OCH(CH₃)₂. In embodiments, R^(10.1) is independently—OCH₃. In embodiments, R^(10.1) is independently hydrogen. Inembodiments, R^(10.1) is independently unsubstituted C₁-C₈ alkoxy. Inembodiments, R^(10.1) is independently unsubstituted C₁-C₆ alkoxy. Inembodiments, R^(10.1) is independently unsubstituted C₁-C₄ alkoxy.

In embodiments, R^(10.1) is independently hydrogen, oxo, halogen, —CF₃,—CBr₃, —CCl₃, —Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂,—OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-Cg alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, 10° ² is independently hydrogen, halogen, —CX^(10.2) ₃,—CHX^(10.2) ₂, —CH₂X^(10.2), —OCX^(10.2) ₃, —OCH₂X^(10.2), —OCHX^(10.2)₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),R²⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl) , R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl (e g, C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R²⁸-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(10.2) ishalogen, —CX^(10.2) ₃, —CHX^(10.2) ₂, —CH₂X^(10.2), —OCX^(10.2) ₃,—OCH₂X^(10.2), —OCHX^(10.2) ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10),—NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), unsubstituted alkyl (e.g.,C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X^(10.2) isindependently halogen. In embodiments, X¹⁰² is independently —F. Inembodiments, X^(10.2) is independently —Cl. In embodiments, X^(10.2) isindependently —Br. In embodiments, X^(10.2) is independently —I.

In embodiments, R^(10.2) is independently halogen. In embodiments,R^(10.1) is independently —CX^(10.2). In embodiments, R^(10.2) isindependently —CHX^(10.2). In embodiments, R^(10.2) is independently—CH₂X^(10.2). In embodiments, R^(10.2) is independently —OCX^(10.2). Inembodiments, R^(10.2) is independently —OCH₂X^(10.2). In embodiments,R^(10.1) is independently —OCHX^(10.2) ₂. In embodiments, R¹⁰² isindependently —CN. In embodiments, R^(10.2) is independently—SO_(n10)R^(10D). In embodiments, R^(10.2) is independently —SR^(10D) .In embodiments, R^(10.2) is independently —SO₂R^(10D). In embodiments,R^(10.2) is independently —SO_(v10)NR^(10A)R^(10B). In embodiments,R^(10.2) is independently —SO₂NR^(10A)R^(10B). In embodiments, R^(10.2)is independently —NHC(O)NR^(10A)R^(10B). In embodiments, R^(10.2) isindependently —N(O)_(m10). In embodiments, R^(10.2) is independently—NR^(10A)R^(10B). In embodiments, R^(10.2) is independently—C(O)R^(10C). In embodiments, R^(10.2) is independently —C(O)—OR^(10C).In embodiments, R^(10.2) is independently —C(O)NR^(10A)R^(10b). Inembodiments, R^(10.2) is independently —OR^(10D) In embodiments,R^(10.2) is independently —NR^(10A)SO₂R_(10D). In embodiments, R^(10.2)is independently —NR^(10A)C(O)R^(10C). In embodiments, R^(10.2) isindependently —NR^(10A)C(O)OR^(10C). In embodiments, R^(10.2) isindependently —NR^(10A)OR^(10C). In embodiments, R^(10.2) isindependently methoxy. In embodiments, R^(10.2) is independently ethoxy.In embodiments, R^(10.2) is independently propoxy. In embodiments,R^(10.2) is independently butoxy. In embodiments, R^(10.2) isindependently pentoxy. In embodiments, R^(10.2) is independently —F. Inembodiments, R^(10.2) is independently —Cl. In embodiments, 10.2 isindependently —Br. In embodiments, R^(10.2) is independently —I. Inembodiments, R^(10.2) is independently oxo. In embodiments, R^(10.2) isindependently halogen. In embodiments, R^(10.2) is independently —CCl₃.In embodiments, R^(10.2) is independently —CBr₃. In embodiments,R^(10.2) is independently —CF₃. In embodiments, R^(10.2) isindependently —CI₃. In embodiments, R^(10.2) is independently CHCl₂. Inembodiments, R^(10.2) is independently —CHBr₂. In embodiments, R¹⁰ ² isindependently —CHF₂. In embodiments, R^(10.2) is independently —CHI₂. Inembodiments, R^(10.2) is independently —CH₂Cl In embodiments, R^(10.2)is independently —CH₂Br. In embodiments, R^(10.2) is independently—CH₂F. In embodiments, R^(10.2) is independently —CH₂I. In embodiments,R^(10.2) is independently —CN. In embodiments, R¹⁰ ² is independently—OH. In embodiments, R^(10.2) is independently —NH₂. In embodiments,R^(10.2) is independently —COOH. In embodiments, R^(10.2) isindependently —CONH₂. In embodiments, R^(10.2) is independently —NO₂. Inembodiments, R^(10.2) is independently —SH. In embodiments, R^(10.2) isindependently —SO₃H. In embodiments, R^(10.2) is independently —SO₄H. Inembodiments, R^(10.2) is independently —SO₂NH₂. In embodiments, R^(10.2)is independently —NHNH₂. In embodiments, R^(10.2) is independently—ONH₂. In embodiments, R^(10.2) is independently —NHC(O)NHNH₂. Inembodiments, R^(10.2) is independently —NHC(O)NH₂. In embodiments,R^(10.2) is independently —NHSO₂H. In embodiments, R^(10.2) isindependently —NHC(O)H. In embodiments, R^(10.2) is independently—NHC(O)OH. In embodiments, R^(10.2) is independently —NHOH. Inembodiments, R^(10.2) is independently —OCCl₃. In embodiments, R^(10.2)is independently —OCF₃. In embodiments, R^(10.2) is independently—OCBr₃. In embodiments, R^(10.2) is independently —OCI₃. In embodiments,R^(10.2) is independently —OCHCl₂. In embodiments, R^(10.2) isindependently —OCHBr₂. In embodiments, R^(10.2) is independently —OCHI₂.In embodiments, R^(10.2) is independently —OCHF₂. In embodiments,R^(10.2) is independently —OCH₂Cl In embodiments, R^(10.2) isindependently —OCH₂Br. In embodiments, R^(10.2) is independently —OCH2I.In embodiments, R^(10.2) is independently —OCH₂F. In embodiments,R^(10.2) is independently —N₃. In embodiments, R^(10.2) is independently—CH₃. In embodiments, R^(10.2) is independently —OCH(CH₃)₂. Inembodiments, R^(10.2) is independently —OCH₃. In embodiments, R^(10.2)is independently hydrogen. In embodiments, R^(10.2) is independentlyunsubstituted C₁-C₈ alkoxy. In embodiments, R^(10.2) is independentlyunsubstituted C₁-C₆ alkoxy. In embodiments, R^(10.2) is independentlyunsubstituted C₁-C₄ alkoxy.

In embodiments, R^(10.3) is independently hydrogen, oxo, halogen, —CF₃,—CBr₃, —CCl₃, —Cl₃—CHF₂, —CHBr₂, —CHCl_(2,)—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂,—OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁰ ⁻³ is independently hydrogen, halogen, —CX^(10.3) ₃,—CHX^(10.3) ₂, —CH₂X^(10.3), —OCX^(10.3) ₃, —OCH₂X^(10.3), —OCHX^(10.3)₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D),—NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C),—NR^(10A)OR^(10C), —NR^(10A)OR^(10C), R²⁸-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R²⁸-substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R²⁸-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R²⁸-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl),

R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R²⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R^(10.3) is halogen, —CX^(10.3) ₃,—CHX^(10.3) ₂, —CH₂X^(10.3), —OCX^(10.3) ₃, —OCH₂X^(10.3), —OCHX^(10.3)₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),unsubstituted alkyl (e.g., C₁-C₈ alkyl, C ₁-C₆ alkyl, or C₁-C₄ alkyl),unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstitutedcycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X^(10.3) isindependently halogen. In embodiments, X^(10 .3) is independently —F. Inembodiments, X¹⁰⁻³ is independently —Cl. In embodiments, X^(10.3) isindependently —Br. In embodiments, X¹⁰⁻³ is independently —I.

In embodiments, R^(10.3) is independently halogen. In embodiments,R^(10.3) is independently —CX^(10.3) ₃. In embodiments, R^(10.3) isindependently —CHX^(10.3) ₂. In embodiments, R^(10.3) is independently—CH₂X^(10.3). In embodiments, R^(10.3) is independently —OCX^(10.3) ₃.In embodiments, R^(10.3) is independently —OCH₂X^(10.3). In embodiments,R^(10.3) is independently —OCHX^(10.3) ₂. In embodiments, R^(10.3) isindependently —CN. In embodiments, R^(10.3) is independently—SO^(n10)R^(10D). In embodiments, R^(10.3) is independently —SR^(10D).In embodiments, R^(10.3) is independently —OCH₂X^(10.3). In embodiments,R^(10.3) is independently —SO_(v10)NR^(10A)R^(10B). In embodiments,R^(10. 3) is independently —SO₂NR^(10A)R^(10B). In embodiments, R^(10.3)is independently —NHC(O)NR^(10A)R^(10B). In embodiments, R^(10.3) isindependently —N(O)_(m10). In embodiments, R^(10.3) is independently—NR^(10A)R^(10B). In embodiments, R^(10.3) is independently—C(O)R^(10C). In embodiments, R^(10.3) is independently —C(O)—OR^(10C).In embodiments, R^(10.3) is independently —C(O)NR^(10A)R^(10B). Inembodiments, R^(10.3) is independently —OR^(10D). In embodiments,R^(10.3) is independently —NR^(10A)SO₂R^(10D). In embodiments, R^(10.3)is independently —NR^(10A)C(O)R^(10C). In embodiments, R^(10.3) isindependently —NR^(10A)C(O)OR^(10C). In embodiments, R^(10.3) isindependently —NR^(10A)OR^(10C). In embodiments, R^(10.3) isindependently methoxy. In embodiments, R^(10.3) is independently ethoxy.In embodiments, R^(10.3) is independently propoxy. In embodiments,R^(10.3) is independently butoxy. In embodiments, R^(10.3) isindependently pentoxy. In embodiments, R^(10.3) is independently —F. Inembodiments, R^(10.3) is independently —Cl. In embodiments, R^(10.3) isindependently —Br. In embodiments, R^(10.3) is independently —I. Inembodiments, R^(10.3) is independently oxo. In embodiments, R^(10.3) isindependently halogen. In embodiments, R^(10.3) is independently —CCl₃.In embodiments, R^(10.) is independently —CBr₃. In embodiments, R^(10.3)is independently —CF₃. In embodiments, R^(10.3) is independently —CI₃.In embodiments, R^(10.3) is independently CHCl₂. In embodiments,R^(10.3) is independently —CHBr₂. In embodiments, R^(10.3) isindependently —CHF₂. In embodiments, R^(10.3) is independently —CHI₂. Inembodiments, R^(10.3) is independently —CH₂Cl. In embodiments, R^(10.3)is independently —CH₂Br. In embodiments, R^(10.3) is independently—CH₂F. In embodiments, R^(10.3) is independently —CH₂I. In embodiments,R^(10.3) is independently —CN. In embodiments, R^(10.3) is independently—OH. In embodiments, R^(10.3) is independently —NH₂. In embodiments,R^(10.3) is independently —COOH. In embodiments, R^(10.3) isindependently —CONH₂. In embodiments, R^(10.3) is independently —NO₂. Inembodiments, R^(10.3) is independently —SH. In embodiments, R^(10.3) isindependently —SO₃H. In embodiments, R^(10.3) is independently —SO₄H. Inembodiments, R^(10.3) is independently —SO₂NH₂. In embodiments, R^(10.3)is independently —NHNH₂. In embodiments, R^(10.3) is independently—ONH₂. In embodiments, R^(10.3) is independently —NHC(O)NHNH₂. Inembodiments, R^(10.3) is independently —NHC(O)NH₂. In embodiments, R¹⁰⁻³is independently —HNSO₂H. In embodiments, R^(10.3) is independently—NHC(O)H. In embodiments, R^(10.3) is independently —NHC(O)OH. Inembodiments, R^(10.3) is independently —NHOH. In embodiments, R^(10.3)is independently —OCCl₃. In embodiments, R^(10.3) is independently—OCF₃. In embodiments, R^(10.3) is independently —OCBr₃. In embodiments,R^(10.3) is independently —OCI₃. In embodiments, R^(10.3) isindependently —OCHCl₂. In embodiments, R^(10.3) is independently—OCHBr₂. In embodiments, R^(10.3) is independently —OCHI₂. Inembodiments, R^(10.3) is independently —OCHF₂. In embodiments, R^(10.3)is independently —OCH₂Cl In embodiments, R^(10.3) is independently—OCH₂Br. In embodiments, R^(10.3) is independently —OCH₂I. Inembodiments, R^(10.3) is independently —OCH₂F. In embodiments, R^(10.3)is independently —N₃. In embodiments, R^(10.3) is independently —CH₃. Inembodiments, R^(10.3) is independently OCH(CH₃)₂. In embodiments,R^(10.3) is independently OCH₃. In embodiments, R^(10.3) isindependently hydrogen. In embodiments, R^(10.3) is independentlyunsubstituted C₁-C₈ alkoxy. In embodiments, R^(10.3) is independentlyunsubstituted C₁-C₆ alkoxy. In embodiments, R^(10.3) is independentlyunsubstituted C₁-C₄ alkoxy.

In embodiments, R^(10.4) is independently hydrogen, oxo, halogen, -CF₃,-CBr₃, —CCl₃, —Cl₃-CHF2,-CHBr2,-CHC12,-CHI₂, -CH₂F, -CH₂Br, -CH₂Cl,—CH2I, -OCF3,-OCBr3,-OCC13, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂,—OCH₂F, -OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, -S 02NH₂, NHNH₂, ONH₂, NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R^(10A) is independently hydrogen, halogen,—CX^(10.4) ₃,—CHX^(10.4) ₂, —CH₂X^(10.4), —OCX^(10.4) ₃, —OCH₂X^(10.4), —OCHX^(10.4)₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),R²⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R²⁸-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(10.4) ishalogen, —CX^(10.4) ₃, —CHX^(10.4) ₂, —CH₂X^(10.4), —OCX^(10.4) ₃,—OCH₂X^(10.4), —OCHX^(10.4) ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10),—NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl) unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X^(10.4) isindependently halogen. In embodiments, X^(10.4) is independently —F. Inembodiments, X¹¹¹⁴ is independently —Cl. In embodiments, X¹⁰ ′ isindependently —Br. In embodiments, X^(m-4) is independently —I.

In embodiments, R^(10.4) is independently halogen. In embodiments,R^(10.4) is independently —CX^(10.4) ₃. In embodiments, R^(10.4) isindependently —CHX^(10.4) ₂. In embodiments, R^(10.4) is independently—CH₂X^(10.4). In embodiments, R^(10.4) is independently —OCX^(10.4) ₃.In embodiments, R^(10.4) is independently —OCH₂X^(10.4). In embodiments,R^(10.4) is independently —OCHX^(10.4) ₂. In embodiments, R^(10.4) isindependently —CN. In embodiments, R^(10.4) is independently—SO_(n10)R^(10D). In embodiments, R^(10.4) is independently —SR^(10D).In embodiments, R^(10.4) is independently —SO₂R^(10D). In embodiments,R^(10.4) is independently —SO_(v10)NR^(10A)R^(10B). In embodiments,R^(10.4) is independently —SO₂NR^(10A)R^(10B). In embodiments, R^(10.4)is independently —NHC(O)NR^(10A)R^(10B). In embodiments, R^(10.4) isindependently —N(O)_(m10). In embodiments, R^(10.4) is independently—NR^(10A)R^(10B). In embodiments, R^(10.4) is independently -13C(O)R^(10C). In embodiments, R^(10.4) is independently —C(O)—OR^(10C).In embodiments, R^(10.4) is independently —C(O)NR^(10A)R^(10B). Inembodiments, R^(10.4) is independently —OR^(10D) In embodiments,R^(10.4) is independently —NR^(10A)SO₂R^(10D). In embodiments, R^(10.4)is independently —NR^(10A)C(O)R^(10C). In embodiments, R^(10.4) isindependently —NR^(10A)C(O)OR^(10C). In embodiments, R^(10.4) isindependently —NR^(10A)OR^(10C). In embodiments, R^(10.4) isindependently methoxy. In embodiments, R^(10.4) is independently ethoxy.In embodiments, R^(10.4) is independently propoxy. In embodiments,R^(10.4) is independently butoxy. In embodiments, R^(10.4) isindependently pentoxy. In embodiments, R^(10.4) is independently —F. Inembodiments, R^(10.4) is independently —Cl. In embodiments, R^(10.4) isindependently —Br. In embodiments, R^(10.4) is independently —I. Inembodiments, R^(10.4) is independently oxo. In embodiments, R^(10.4) isindependently halogen. In embodiments, R^(10.4) is independently —CCl₃.In embodiments, R^(10.4) is independently —CBr₃. In embodiments,R^(10.4) is independently —CF₃. In embodiments, R^(10A) is independently—CI₃. In embodiments, R^(10.4) is independently CHCl₂. In embodiments,R^(10.4) is independently —CHBr₂. In embodiments, R^(10.4) isindependently —CHF₂. In embodiments, R^(10.4) is independently —CHI₂. Inembodiments, R^(10.4) is independently —CH₂Cl. In embodiments, R^(10.4)is independently —CH₂Br. In embodiments, R^(10.4) is independently —CH₂F. In embodiments, R^(10.4) is independently —CH₂I. In embodiments,R^(10.4) is independently —CN. In embodiments, R^(10.4) is independently—OH. In embodiments, R^(10.4) is independently —NH2. In embodiments,R^(10.4) is independently —COOH. In embodiments, R^(10.4) isindependently —CONH₂. In embodiments, R^(10.4) is independently —NO₂. Inembodiments, R¹⁰ .4 is independently —SH. In embodiments, R^(10.4) isindependently —SO₃H. In embodiments, R¹⁰ .4 is independently —SO₄H. Inembodiments, R^(10.4) is independently —SO2NH2. In embodiments, R^(10.4)is independently ——NHNH₂. In embodiments, R^(10.4) is independently—ONH₂. In embodiments, R^(10.4) is independently —NHC(O)NHNH₂. Inembodiments, R^(10.4) is independently —NHC(O)NH₂. In embodiments, R¹⁰⁻⁴is independently —HNSO₂H. In embodiments, R^(10.4) is independently—NHC(O)H. In embodiments, R^(10.4) is independently —NHC(O)OH. Inembodiments, R^(10.4) is independently —NHOH. In embodiments, R^(10.4)is independently —OCCl₃. In embodiments, R^(10.4) is independently—OCF₃. In embodiments, R^(10.4) is independently —OCBr₃. In embodiments,R^(10.4) is independently —OCI₃. In embodiments, R^(10.4) isindependently —OCHCl₂. In embodiments, R^(10.4) is independently—OCHBr₂. In embodiments, R^(10.4) is independently —OCHI₂. Inembodiments, R^(10.4) is independently —OCHF₂. In embodiments, R^(10.4)is independently —OCH₂Cl In embodiments, R^(10.4) is independently—OCH₂Br. In embodiments, R^(10.4) is independently —OCH₂I. Inembodiments, R^(10.4) is independently —OCH₂F. In embodiments, R^(10.4)is independently —N₃. In embodiments, R^(10.4) is independently —CH₃. Inembodiments, R^(10.4) is independently —OCH(CH₃)₂. In embodiments,R^(10.4) is independently —OCH₃. In embodiments, R^(10.4) isindependently hydrogen. In embodiments, R^(10.4) is independentlyunsubstituted C₁-C₈ alkoxy. In embodiments, R^(10.4) is independentlyunsubstituted C₁-C₆ alkoxy. In embodiments, R^(10.4) is independentlyunsubstituted C₁-C₄ alkoxy.

In embodiments, R¹⁰ ⁻⁵ is independently hydrogen, oxo, halogen, —CF₃,—CBr₃, —CCl₃, —CI₃—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OCF₃, —OCBr₃, —OCCl₃, —OCI₃, —OCHF₂, —OCHBr₂,—OCHCl₂, —OCHI₂,—OCH₂F, —OC H₂Br, —OCH₂Cl, —OCH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted orunsubstituted alkyl (e.g., C₁-Cs alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R¹⁰ ⁵ is independently hydrogen, halogen, —CX^(10.5) ₃,—CHX^(10.5) ₂, —CH₂X^(10.5), —OCX^(10.5) ₃, —OCH₂X^(10.5), —OCHX^(10.5)₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),R²⁸-substituted or unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R²⁸-substituted or unsubstituted heteroalkyl (e.g., 2to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4membered heteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl(e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),R²⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), R²⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀ aryl, or phenyl), or R²⁸-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R^(10.5) ishalogen, —CX^(10.5) ₃, —CHX^(10.5) ₂, —CH₂X^(10.5), —OCX^(10.5) ₃,—OCH₂X^(10.5), —OCHX^(10.5) ₂, —CN, —SO_(n10)R^(10D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10),—NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D), —NR^(10A)C(O)R^(10C),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹⁰⁻⁵ isindependently halogen. In embodiments, X^(10.5) is independently —F. Inembodiments, X^(10.5) is independently —Cl. In embodiments, X^(10.5) isindependently —Br. In embodiments, X^(10.5) is independently —I.

In embodiments, R^(10.5) is independently halogen. In embodiments,R^(10.5) is independently —CX^(10.5) ₃. In embodiments, R^(10.5) isindependently —CHX^(10.5) In embodiments, R^(10.5) is independently—CH₂X^(10.5). In embodiments, R^(10.5) is independently —OCX^(10.5). Inembodiments, R^(10.5) is independently —OCH₂X^(10.5). In embodiments,R^(10.5) is independently —OCHX^(10.5). In embodiments, R^(10.5) isindependently —CN. In embodiments, R^(10.5) is independently—SO_(n10)R^(10D). In embodiments, R^(10.5) is independently —SR^(10D).In embodiments, R^(10.5) is independently —SO₂R^(10D). In embodiments,R^(10.5) is independently —SO_(v10)NR^(10A)R^(10B). In embodiments,R^(10.5) is independently —SO₂NR^(10A)R^(10B). In embodiments, R^(10.5)is independently —NHC(O)NR^(10A)R^(10B). In embodiments, R^(10.5) isindependently —N(O)_(m10). In embodiments, R^(10.5) is independently—NR^(10A)R^(10B). In embodiments, R^(10.5) is independently—C(O)R^(10C). In embodiments, R^(10.5) is independently —C(O)—OR^(10C).In embodiments, R^(10.5) is independently —C(O)NR^(10A)R^(10B). Inembodiments, R^(10.5) is independently —OR^(10D). In embodiments,R^(10.5) is independently —NR^(10A)SO₂R^(10D). In embodiments, R^(10.5)is independently —NR^(10A)C(O)R^(10C). In embodiments, R^(10.5) isindependently —NR^(10A)C(O)R^(10C). In embodiments, R^(10.5) isindependently —NR^(10A)OR^(10C). In embodiments, R^(10.5) isindependently methoxy. In embodiments, R^(10.5) is independently ethoxy.In embodiments, R^(10.5) is independently propoxy. In embodiments,R^(10.5) is independently butoxy. In embodiments, R^(10.5) isindependently pentoxy. In embodiments, R^(10.5) is independently —F. Inembodiments, R^(10.5) is independently —Cl. In embodiments, R^(10.5) isindependently —Br. In embodiments, R^(10.5) is independently —I. Inembodiments, R^(10.5) is independently oxo. In embodiments, R^(10.5) isindependently halogen. In embodiments, R^(10.5) is independently —CCl₃.In embodiments, R^(10.5) is independently —CBr₃. In embodiments,R^(10.5) is independently —CF₃. In embodiments, R^(10.5) isindependently —CI₃. In embodiments, R^(10.5) is independently CHCl₂. Inembodiments, R^(10.5) is independently —CHBr₂. In embodiments, R^(10.5)is independently —CHF₂. In embodiments, R^(10.5) is independently —CHI₂.In embodiments, R^(10.5) is independently —CH₂Cl. In embodiments,R^(10.5) is independently —CH₂Br. In embodiments, R^(10.5) isindependently —CH₂F. In embodiments, R^(10.5) is independently —CH₂I. Inembodiments, R^(10.5) is independently —CN. In embodiments, R^(10.5) isindependently —OH. In embodiments, R^(10.5) is independently —NH₂. Inembodiments, R^(10.5) is independently —COOH. In embodiments, R^(10.5)is independently —CONH₂. In embodiments, R^(10.5) is independently —NO₂.In embodiments, R^(10.5) is independently —SH. In embodiments, R^(10.5)is independently —SO₃H. In embodiments, R^(10.5) is independently —SO₄H.In embodiments, R^(10.5) is independently —SO₂NH₂. In embodiments,R^(10.5) is independently —NHNH₂. In embodiments, R^(10.5) isindependently —ONH₂. In embodiments, R^(10.5) is independently—NHC(O)NHNH₂. In embodiments, R^(10.5) is independently —NHC(O)NH₂. Inembodiments, R^(10.5) is independently —HNSO₂H. In embodiments, R^(10.5)is independently —NHC(O)H. In embodiments, R^(10.5) is independently—NHC(O)OH. In embodiments, R^(10.5)is independently —NHOH. Inembodiments, R^(10.5) is independently —OCCl₃. In embodiments, R^(10.5)is independently —OCF₃. In embodiments, R^(10.5) is independently—OCBr₃. In embodiments, R^(10.5) is independently —OCI₃. In embodiments,R^(10.5) is independently —OCHCl₂. In embodiments, R^(10.5) isindependently —OCHBr₂. In embodiments, R^(10.5) is independently —OCHI₂.In embodiments, R^(10.5) is independently —OCHF₂. In embodiments,R^(10.5) is independently —OCH₂Cl In embodiments, R^(10.5) isindependently —OCH₂Br. In embodiments, R^(10.5) is independently —OCH₂I.In embodiments, R^(10.5) is independently —OCH₂F. In embodiments,R^(10.5) is independently —N₃. In embodiments, R^(10.5) is independentlyCH₃. In embodiments, R^(10.5) is independently OCH(CH₃)₂. Inembodiments, R^(10.5) is independently OCH₃. In embodiments, R^(10.5) isindependently hydrogen. In embodiments, R^(10.5) is independentlyunsubstituted C₁-Cg alkoxy. In embodiments, R^(10.5) is independentlyunsubstituted C₁-C₆ alkoxy. In embodiments, R^(10.5) is independentlyunsubstituted C₁-C₄ alkoxy.

In embodiments, X, X³, X⁷, X⁹, and X¹⁰ are independently —F, —Cl, —Br,or —I. In embodiments, X is F. In embodiments, X is Cl. In embodiments,X is Br. In embodiments, X is I.

In embodiments, X¹ is F. In embodiments, X¹ is Cl. In embodiments, X¹ isBr. In embodiments, X¹ is I. In embodiments, X² is F. In embodiments, X²is Cl. In embodiments, X² is Br. In embodiments, X² is I. Inembodiments, X³ is F. In embodiments, X³ is Cl. In embodiments, X³ isBr. In embodiments, X³ is I. In embodiments, X⁴ is F. In embodiments, X⁴is Cl. In embodiments, X⁴ is Br. In embodiments, X⁴ is I. Inembodiments, X⁵ is F. In embodiments, X⁵ is Cl. In embodiments, X⁵ isBr. In embodiments, X⁵ is I. In embodiments, X⁶ is F. In embodiments, X⁶is Cl. In embodiments, X⁶ is Br. In embodiments, X⁶ is I. Inembodiments, X⁷ is F. In embodiments, X⁷ is Cl. In embodiments, X⁷ isBr. In embodiments, X⁷ is I. In embodiments, X⁸ is F. In embodiments, X⁸is Cl. In embodiments, X⁸ is Br. In embodiments, X⁸ is I. Inembodiments, X⁹ is F. In embodiments, X⁹ is Cl. In embodiments, X⁹ isBr. In embodiments, X⁹ is I. In embodiments, X¹⁰ is F. In embodiments,X¹⁰ is Cl. In embodiments, X¹⁰ is Br. In embodiments, X¹⁰ is I. Inembodiments, X²¹ is F. In embodiments, X²¹ is Cl. In embodiments, X²¹ isBr. In embodiments, X²¹ is I.

In embodiments, z7 is 0. In embodiments, z7 is 1. In embodiments, z7 is2. In embodiments, z7 is 3. In embodiments, z7 is 4. In embodiments, z7is 5. In embodiments, z9 is 0. In embodiments, z9 is 1. In embodiments,z9 is 2. In embodiments, z9 is 3. In embodiments, z9 is 4. Inembodiments, z9 is 5. In embodiments, z10 is 0. In embodiments, z10is 1. In embodiments, z10 is 2. In embodiments, z10 is 3. Inembodiments, z10 is 4. In embodiments, z10 is 5. In embodiments, z21 is0. In embodiments, z21 is 1. In embodiments, z21 is 2. In embodiments,z21 is 3. In embodiments, z21 is 4. In embodiments, z21 is 5.

In embodiments, n3 is 0. In embodiments, n3 is 1. In embodiments, n3 is2. In embodiments, n3 is 3. In embodiments, n3 is 4. In embodiments, n7is 0. In embodiments, n7 is 1. In embodiments, n7 is 2. In embodiments,n7 is 3. In embodiments, n7 is 4. In embodiments, n9 is 0. Inembodiments, n9 is 1. In embodiments, n9 is 2. In embodiments, n9 is 3.In embodiments, n9 is 4. In embodiments, n10 is 0. In embodiments, n10is 1. In embodiments, n10 is 2. In embodiments, n10 is 3. Inembodiments, n10 is 4. In embodiments, n21 is 0. In embodiments, n21is 1. In embodiments, n21 is 2. In embodiments, n21 is 3. Inembodiments, n21 is 4.

In embodiments, m3 is 1. In embodiments, m3 is 2. In embodiments, v3is 1. In embodiments, v3 is 2. In embodiments, m7 is 1. In embodiments,m7 is 2. In embodiments, v7 is 1. In embodiments, v7 is 2. Inembodiments, m9 is 1. In embodiments, m9 is 2. In embodiments, v9 is 1.In embodiments, v9 is 2. In embodiments, m10 is 1. In embodiments, m10is 2. In embodiments, v10 is 1. In embodiments, v10 is 2. Inembodiments, m21 is 1.

In embodiments, m21 is 2. In embodiments, v21 is 1. In embodiments, v21is 2.

Ring A may be cycloalkyl. Ring A may be C₃-C₈ cycloalkyl.

Ring A may be 3 to 8 membered heterocycloalkyl. Ring A may be a 4 to 6membered heterocycloalkyl. Ring A may be a 5 or 6 memberedheterocycloalkyl. Ring A may be 5 membered heterocycloalkyl. Ring A maybe 6 membered heterocycloalkyl.

In embodiments, Ring A is a C₆-C₁₂ aryl. In embodiments, Ring A is aC₆-C₁₀ aryl. IIn embodiments, Ring A is phenyl. In embodiments, Ring Ais naphthyl. In embodiments, Ring A is biphenyl.

In embodiments, Ring A is 5 to 10 membered heteroaryl. In embodiments,Ring A is a 5 to 6 membered heteroaryl. In embodiments, Ring A is 5membered heteroaryl. In embodiments, Ring A is 6 membered heteroaryl.

In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is pyrazolyl.In embodiments, Ring A is imidazolyl. In embodiments, Ring A is thienyl.In embodiments, Ring A is thiophenyl. In embodiments, Ring A is thienyl.In embodiments, Ring A is oxazolyl. In embodiments, Ring A isisoxazolyl. In embodiments, Ring A is isothiazolyl. In embodiments, RingA is thiazolyl. In embodiments, Ring A is oxadiazolyl. In embodiments,Ring A is pyridyl. In embodiments, Ring A is pyridazinyl. Inembodiments, Ring A is pyrimidinyl. In embodiments, Ring A is pyrazinyl.In embodiments, Ring A is triazinyl. In embodiments, Ring A is indolyl.In embodiments, Ring A is benzofuranyl. In embodiments, Ring A isnaphthyl. In embodiments, Ring A is tetrahydronaphthyl. In embodiments,Ring A is dihydrobenzopyranyl. In embodiments, Ring A is2,3-dihydro-1H-indenyl.

In embodiments, the compound is

In embodiments, the compound is a compound described herein (e.g., in anaspect, embodiment, example, figures, table, or claim).

In embodiments, the compound is A2-26, A2-27, A2-28, A2-60, A2-29,A2-35, A2-36, A2-61, A2-38, A2-37, A2-63, A2-64, KZ-1-18, KZ-1-39,KZ-1-14, KZ-1-16, KZ-1-15, KZ-1-26, KZ-1-20, KZ-1-30, KZ-1-23, A2-72,A2-39, KZ-1-34, KZ-1-38, KZ-1-17, KZ-1-36, KZ-1-3, A2-123, A2-124,A2-125, A2-126, A2-127, A2-128, A2-129, A2-130, A2-131, A2-132, A2-133,A2-134, A2-143, KZ-1-9, KZ-1-37, KZ-1-32, KZ-1-33, KZ-1-12, KZ-1-13,KZ-1-11, KZ-1-25, A2-73, KZ-1-19, KZ-1-40, A2-70, A2-71, KZ-1-27,KZ-1-22, A2-83, A2-87, A2-84, A2-85, A2-86, KZ-1-21, A2-154, A2-155,A2-156, A2-157, A2-170, A2-171, A2-172, A2-173, A2-174, A2-175, A2-176,A2-177, A2-178, A2-179, A2-180, A2-181, A2-144, A2-145 A2-152, A2-153,A2-189, A2-190, A2-191, A2-192, A2-193, A2-194, A2-202, A2-203, A2-204,A2-207, A2-208, KZ-1-80, or KZ-1-81.

In embodiments, the compound is A2-29, A2-123, A2-124, A2-125, A2-126,A2-130, A2-85, A2-171, or A2-172.

In embodiments, the compound is

In some embodiments, a compound as described herein may include multipleinstances of R⁷, R¹⁰, and/or other variables. In such embodiments, eachvariable may optional be different and be appropriately labeled todistinguish each group for greater clarity. For example, where each R²¹,R⁷, R⁹, and/or R¹⁰ is different, they may be referred to, for example,as R^(21.1), R^(21.2), R^(21.3), R^(21.4), R^(21.5), R^(7.1), R^(7.2),R^(7.3), R^(7.4), R^(7.5), R^(9.1), R^(9.2), R^(9.3), R^(9.4), R^(9.5),R ^(10.1), R^(10.2), R^(10.3), R^(10.4), R^(10.5), R^(10.6), R^(10.7),R^(10.8), R^(10.9,) respectively, wherein the definition of R²¹ isassumed by R^(21.1), R^(21.2), R^(21.3), R^(21.4), R^(21.5); R⁷ isassumed by R^(7.1), R^(7.2), R^(7.3), R^(7.4), R^(7.5); R⁹ is assumed byR^(9.1), R^(9.2), R^(9.3), R^(9.4), R^(9.5); R¹⁰ is assumed by R^(10.1),R^(10.2), R^(10.3), R^(10.4), R^(10.5), R^(10.6), R10.7, R^(10.8),R^(10.9.) The variabels used within a definition of R²¹, R⁷, R⁹, R¹⁰,and/or other variables that appear at multiple instances and aredifferent may similarly be appropriately labeled to distinguish eachgroup for greater clarity. In some embodiments, the compound is acompound described herein (e.g., in an aspect, embodiment, example,claim, or table).

In embodiments, the compound is not a compound described in Jpn. KokaiTokkyo

Koho (2003), JP 2003277340 A 20031002, JP 2003277340, or laid open JPapplication JP 2003277340, each of which is incorporated by reference itits entirety for all purposes.

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptabR¹ salt thereof,and a pharmaceutically acceptable excipient.

In embodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, is included in atherapeutically effective amount.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent) in atherapeutically effective amount. In embodiments of the pharmaceuticalcompositions, the second agent is an agent for treating asthma. Inembodiments, the second agent is an anti-inflammatory agent. Inembodiments, the second agent is an anti-autoimmune disease agent.

IV. Methods of Use

In an aspect is provided a method of treating asthma, the methodincluding administering to a subject in need thereof an effective amountof an integrin α2β1 inhibitor.

In embodiments, the α2β1 inhibitor is a nucleic acid (e.g., DNA, RNA,siRNA, or antisense oligonucleotide), protein (e.g., antibody orantigen-binding fragment thereof), or compound (e.g., compound describedherein).

In an aspect is provided a method of treating asthma, the methodincluding administering to a subject in need thereof an effective amountof a compound, or a pharmaceutically acceptable salt thereof, describedherein.

In embodiments, the compound is

In embodiments, the compound is

In embodiments, compound is

In embodiments, compound is a compound (e.g., genus of compounds orexemplified compound) described in PCT/US06/22225, which is incorporateby reference in its entirety for all purposes. In embodiments, compoundis a compound (e.g., genus of compounds or exemplified compound)described in US 2009/0197861, which is incorporate by reference in itsentirety for all purposes. In embodiments, compound is a compound (e.g.,genus of compounds or exemplified compound) described in U.S. Pat. No.8,258,159, which is incorporate by reference in its entirety for allpurposes. In embodiments, compound is a compound (e.g., genus ofcompounds or exemplified compound) described in Halland, N., H. Blum, etal. (2014). “Small Macrocycles As Highly Active Integrin alpha 2 beta 1Antagonists.” Acs Medicinal Chemistry Letters 5(2): 193-198, which isincorporate by reference in its entirety for all purposes. Inembodiments, compound is a compound (e.g., genus of compounds orexemplified compound) described in Miller, M. W., S. Basra, et al.(2009). “Small-molecule inhibitors of integrin alpha2beta 1 that preventpathological thrombus formation via an allosteric mechanism.” Proc NatlAcad Sci U S A 106(3): 719-724., which is incorporate by reference inits entirety for all purposes. In embodiments, compound is a compound(e.g., genus of compounds or exemplified compound) described in Choi,S., G. Vilaire, et al. (2007). “Small molecule inhibitors of integrinalpha2beta 1.” J Med Chem 50(22): 5457-5462., which is incorporate byreference in its entirety for all purposes.

Provided herein are methods for treating asthma. In embodiments, theasthma is severe asthma. In embodiments, the asthma is acute severeasthma. In embodiments, the asthma is moderate asthma. In one aspect, isa method for treating asthma by administering to a subject in needthereof an α2β1-inhibitor (e.g., where the α2β1-inhibitor is a compoundhaving a formulae described herein, including embodiments thereof). Inan embodiment, is a method for treating asthma by administering to asubject in need thereof a therapeutically effective amount of anα2β1-inhibitor, where the α2β1-inhibitor is an α2β1-inhibitor compoundhaving the formulae described herein, including embodiments thereof. Theα2β1-inhibitor compound may be a compound having a formula describedherein, including embodiments thereof. The α2β1-inhibitor compound maybe a pharmaceutical composition as described herein, includingembodiments thereof.

In an embodiment, is a method for treating asthma by administering to asubject in need thereof a therapeutically effective amount of anα2β1-inhibitor wherein the administering is by inhalation.

In an aspect is provided a method of treating an inflammatory diseaseincluding administering to a subject in need thereof an effective amountof a compound described herein.

In embodiments, the inflammatory disease is arthritis, rheumatoidarthritis, psoriatic arthritis, juvenild idiopathic arthritis, multiplesclerosis, systemic lupus erythematosus (SLE), myasthenia gravis,juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosingspondylitis, psoriasis, Sjogren's syndrome,vasculitis,glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis,ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison'sdisease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiacdisease, chronic prostatitis, inflammatory bowel disease, pelvicinflammatory disease, reperfusion injury, ischemia reperfusion injury,stroke, sarcoidosis, transplant rej ection, interstitial cystitis,atherosclerosis, scleroderma, or atopic dermatitis.

In an aspect is provided a method of treating an autoimmune diseaseincluding administering to a subject in need thereof an effective amountof a compound described herein.

In embodiments, the autoimmune disease is arthritis, rheumatoidarthritis, psoriatic arthritis, juvenild idiopathic arthritis, multiplesclerosis, systemic lupus erythematosus (SLE), myasthenia gravis,juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosingspondylitis, psoriasis, Sjogren's syndrome,vasculitis,glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis,ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison'sdisease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiacdisease, chronic prostatitis, inflammatory bowel disease, pelvicinflammatory disease, reperfusion injury, sarcoidosis, transplantrejection, interstitial cystitis, atherosclerosis, scleroderma, oratopic dermatitis.

In embodiments, the method includes administering a second agent (e.g.therapeutic agent). In embodiments, the method includes administering asecond agent (e.g. therapeutic agent) in a therapeutically effectiveamount. In embodiments, the second agent is an anti-inflammatory agent.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

V. Embodiments

Embodiment P1. A compound having the formula:

wherein,

R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

L¹ is a bond or C(O)—;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³,—OCHX³ ₂, —CN, —SO_(n3)R^(3D), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR ^(3A)R^(3B), —C(O)R^(3C),—C(O)—OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D), —NR^(3A)SO₂R^(3D),—NR^(3A)C(O)R^(3C), 13 NR³C(O)OR³, —NR^(3A)OR^(3C), , substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

W¹ is O, S, NR¹;

W² is O, S, NR^(S);

R⁵ is hydrogen or substituted or unsubstituted alkyl;

L² is a bond or —CHR⁶—;

R⁶ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;

W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl;

R⁷ is hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, -OCX⁷ ₃, —OCH₂X⁷,—OCHX⁷ ₂, —CN, —SO_(n7)R^(7D), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7C),—C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)OR^(7C), —NR^(7A)OR^(7C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁸ is hydrogen or substituted or unsubstituted alkyl;

R^(3A), R^(3B),R^(3C) R^(3D), R^(7A), R^(7B), R⁷, and R^(7D) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

each X, X³, and X⁷ are independently —F, —Cl, —Br, or —I;

n3 and n7 are independently an integer from 0 to 3; and

m3, m7, v3 and v7 are independently 1 or 2.

Embodiment P2. The compound of embodiment P1 having the formula:

wherein,

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R²¹ is independently halogen, —CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹, —OCX²¹ ₃,—OCH₂X²¹, —OCHX²¹ ₂, —CN, —SO_(n21)R^(21D), —SO_(v21)NR^(21A)R^(21B),—NHC(O)NR^(21A)R^(3B), —N(O)_(m21), —N R^(21A)R^(21B), —C(O)R^(21C),—C(O)—OR^(21C), —C(O)NR^(21A)R^(21B), —OR^(21D), —NR^(21A)SO₂R^(21D),—NR^(21A)C(O)R^(21C), 13 NR²¹C(O)OR^(21C), —NR^(21A)OR^(21C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl;

z21 is an integer from 0 to 5;

R_(21A), R^(21B), R^(21C), and R^(21D) are independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(21A) and R^(21B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X and X²¹ are independently —F, —Cl, —Br, or —I;

n21 is independently an integer from 0 to 3; and

m21 and v21 are independently 1 or 2.

Embodiment P3. The compound of one of embodiments P1 to P2 wherein R¹ isunsubstituted C₁-C₆ alkyl.

Embodiment P4. The compound of one of embodiments P1 to P2 wherein R¹ is

or substituted or unsubstituted C₄-C₈ alkyl;

wherein,

R¹⁰ is independently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰, —OCX¹⁰ ₃,—OCH₂X¹⁰, —OCHX¹⁰ ₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR ^(10A)R^(10B), —C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹⁰ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(10A), R^(10B), R^(10C), and R^(10D) are independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(10A) and R^(10B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

X and X¹⁰ are independently —F, —Cl, —Br, or —I;

n10 is independently an integer from 0 to 4;

m10 and v10 are independently 1 or 2; and

z10 is an integer from 0 to 5.

Embodiment P5. The compound of one of embodiments P1 to P4 wherein L² is—CHR⁶—;

Embodiment P6. The compound of one of embodiments P1 to P4 wherein L² isa bond.

Embodiment P7. The compound of one of embodiments P1 to P5 wherein R⁶ isunsubstituted alkyl.

Embodiment P8. The compound of one of embodiments P1 to P5 wherein R⁶ ishydrogen.

Embodiment P9. The compound of one of embodiments P1 to P8 wherein W¹ isNH.

Embodiment P10. The compound of one of embodiments P1 to P8 wherein W¹is S.

Embodiment P11. The compound of one of embodiments P1 to P8 wherein W¹is O.

Embodiment P12. The compound of one of embodiments P1 to P11 wherein W²is NH.

Embodiment P13. The compound of one of embodiments P1 to P11 wherein W²is S.

Embodiment P14. The compound of one of embodiments P1 to P11 wherein W²is O.

Embodiment P15. The compound of one of embodiments P1 to P14 wherein W¹and R⁶ are joined to form a substituted or unsubstituted 5 to 6 memberedheterocycloalkyl or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment P16. The compound of one of embodiments P1 to P14 wherein W¹and R⁶ are joined to form a substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment P17. The compound of one of embodiments P1 to P14 wherein W¹and R⁶ are joined to form

Embodiment P18. The compound of one of embodiments P1 to P17 wherein R²,R⁴, R⁵, and R⁸ are hydrogen.

Embodiment P19. The compound of one of embodiments P1 to P18 wherein R³is substituted or unsubstituted C₁-C₆ alkyl.

Embodiment P20. The compound of one of embodiments P1 to P18 wherein R³is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl

Embodiment P21. The compound of one of embodiments P1 to P18 wherein R³is hydrogen.

Embodiment P22. The compound of one of embodiments P1 to P21, wherein L¹is a bond.

Embodiment P23. The compound of one of embodiments P1 to P21, wherein L¹is —C(O)—.

Embodiment P24. The compound of one of embodiments P1 and P3 to P23,wherein R⁷ is unsubstituted C₁-C₆ alkyl.

Embodiment P25. The compound of one of embodiments P1 and P3 to P23,wherein R⁷ is unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment P26. The compound of one of embodiments P2 to P23, whereinRing A is 5 to 6 membered heteroaryl.

Embodiment P27. The compound of one of embodiments P2 to P23, whereinRing A is phenyl.

Embodiment P28. The compound of one of embodiments P2 to P27, whereinz21 is an integer from 1 to 5.

Embodiment P29. The compound of one of embodiments P2 to P27, whereinz21 is 0.

Embodiment P30. The compound of one of embodiments P1 to P29, having theformula:

Embodiment P31. The compound of one of embodiments P1 to P29, having theformula:

Embodiment P32. The compound of one of embodiments P1 to P29, having theformula:

wherein R¹ is

Embodiment P33. The compound of embodiment P32, wherein

wherein z21 is an integer from 0 to 5;

an integer from 0 to 4;

wherein R⁷ is substituted or unsubstituted cycloalkyl;

wherein z21 is an integer from 0 to 3;

wherein z21 is an integer from 0 to 2; or

wherein z21 is an integer from 1 to 5.

Embodiment P34. The compound of one of embodiments P1 to P29, having theformula:

wherein R^(l) is

Embodiment P35. The compound of embodiment P34, wherein

wherein z21 is an integer from 0 to 5;

wherein z21 is an integer from 0 to 4;

wherein R⁷ is substituted or unsubstituted cycloalkyl;

wherein z21 is an integer from 0 to 3; or

wherein z21 is an integer from 0 to 2.

Embodiment P36. The compound of embodiment P1, having the formula:

Embodiment P37. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of one ofembodiments P1 to P36.

Embodiment P38. A method of treating asthma, the method comprisingadministering to a subject in need thereof an effective amount of anintegrin α2β1 inhibitor.

Embodiment P39. The method of embodiment P38, wherein the α2β1inhibitoris a nucleic acid, protein, or compound.

Embodiment P40. The method of embodiment P38, wherein the α2β1 inhibitoris compound of one of embodiments P1 to P36.

Embodiment P41. A method of treating asthma, the method comprisingadministering to a subject in need thereof an effective amount of acompound of one of embodiments P1 to P36.

Embodiment P42. A method of treating asthma, the method comprisingadministering to a subject in need thereof an effective amount of acompound, or a pharmaceutically, having the formula:

wherein,

R¹ substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

L¹ is a bond or —C(O)—;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³,—OCHX³ ₂, —CN, —SO_(n3)R^(3D), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3C),—C(O)—OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D), —NR^(3A)SO₂R^(3D),—NR^(3A)C(O)R^(3C), —NR^(3A)C(O)OR^(3C)—NR^(3A)OR^(3C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

W¹ is O, S, NR⁸;

W² is O, S, NR^(S);

R⁵ is hydrogen or substituted or unsubstituted alkyl;

L² is a bond or —CHR⁶—;

R⁶ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;

W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl;

R⁷ is hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷,—OCHX⁷ ₂, —CN, —SO_(v7)R^(7D), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7C),—C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)OR^(7C), —NR^(7A)OR^(7C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁸ is hydrogen or substituted or unsubstituted alkyl;

R^(3A), R^(3B)B, R^(3C), R^(3D), R^(7A), R^(7B), R^(7C), and R^(7D) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX_(2,)—CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; IC^(A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

each X, X³, and X⁷ are independently —F, —Cl, —Br, or —I; n3 and n7 areindependently an integer from 0 to 3; and m3, m7, v3 and v7 areindependently 1 or 2.

Embodiment P43. The method of embodiment P42, wherein R¹ is

or substituted or unsubstituted C₄-C₈ alkyl;wherein,

R⁹ is independently halogen, —CX⁹ ₃, —CHX⁹ ₂, —CH₂X⁹, —OCX⁹ ₃, —OCH₂X⁹,—OCHX⁹ ₂, —CN, —SO_(n9)R^(9D), —SO_(v9)NR^(9A)R^(9B),—NHC(O)NR^(9A)R^(9B), —N(O)_(m9), —NR^(9A)R^(9B), —C(O)R^(9C),—C(O)—OR^(9C), —C(O)NR^(9A)R^(9B), —OR^(9D), —NR^(9A)SO₂R^(9D),—NR^(9A)C(O)R^(9C), —NR^(9A)C(O)O R^(9C), —NR^(9A)OR^(9C), substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is independently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰ , —OCX¹⁰ ₃,—OCH₂X¹⁰, —OCHX¹⁰ ₂, —CN, —SO_(n10) ^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R_(10B), —N(O)_(m10), —NR^(10A)R^(10B), C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B),—OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A) C(O)OR^(10C), —NR^(10A)OR^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R^(m) substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), and R^(10D)are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(9A) and R^(9B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(10A) and R^(10B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

X, X⁹, and X¹⁰ are independently —F, —Cl, —Br, or —I;

n9 and n10 are independently an integer from 0 to 4;

m9, m10, v9 and v10 are independently 1 or 2;

z9 is an integer from 0 to 5; and

z10 is an integer from 0 to 5.

Embodiment P44. The method of one of embodiments P42 to P43, wherein R¹is

Embodiment P45. The method of embodiment P42, wherein the compound is

Embodiment P46. The method of embodiment P42, wherein the compound is

VI. Additional Embodiments

Embodiment 1. A compound having the formula:

wherein,

R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

L¹ is a bond or —C(O)—;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ _(3,)—OCH₂X³,—OCHX³ ₂, —CN, —SO_(n3)R^(3D), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), —N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3C),—C(O)—OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D), —NR^(3A)SO₂R^(3D),—NR^(3A)C(O)R^(3C), —NR^(3A)C(O)OR^(3C), —NR^(A)OR^(3C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl; or —OR³ is a prodrug moiety;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

W¹ is O, S, NW;

W² is O, S, NR⁵;

R⁵ is hydrogen or substituted or unsubstituted alkyl;

L² is a bond or —C(R⁶)₂—;

R⁶ is hydrogen, ═NH, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl;

W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl;

R⁷ is hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷,—OCHX⁷ ₂, —CN, —SO_(n7)R^(7D), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B)—N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7C),—C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)OR^(7C), —NR^(7A)OR^(7C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁸ is hydrogen or substituted or unsubstituted alkyl;

R^(3A), R_(3B), R^(3C), R^(3D), R^(7A), R^(7B), R^(7C), and R^(7D) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; W^(A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

each X, X³, and X⁷ are independently —F, —Cl, —Br, or —I;

n3 and n7 are independently an integer from 0 to 3; and

m3, m7, v3 and v7 are independently 1 or 2.

Embodiment 2. The compound of embodiment 1 having the formula:

wherein,

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R²¹ is independently halogen, —CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹, —OCX²¹ ₃,—OCH₂X²¹, —OCHX²¹ ₂, —CN, —SO_(n21)R^(21D), —SO_(v21)NR^(21A)R^(21B),—N(O)_(m21), —N R^(21A)R^(21B), —C(O)R^(21C), —C(O)—OR^(21C),—C(O)NR^(21A)R^(21B), —OR^(21D), —NR^(21A)SO₂R^(21D),—NR^(21A)C(O)R^(21C), —NR^(21A)C(O)OR^(21C), —NR^(21A)OR^(21C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl;

z21 is an integer from 0 to 5;

R^(21A), R^(21B), R^(21C), and R^(21D) are independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(21A) and R^(21B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X and X²¹ are independently —F, —Cl, —Br, or —I;

n21 is independently an integer from 0 to 3; and

m21 and v21 are independently 1 or 2.

Embodiment 3. The compound of one of embodiments 1 to 2 wherein R¹ isunsubstituted C₁-C₆ alkyl.

Embodiment 4. The compound of one of embodiments 1 to 2 wherein R¹ is

or substituted or unsubstituted C₄-C₈ alkyl;wherein,

R¹⁰ is independently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰ , —OCX¹⁰ ₃,—OCH₂X¹⁰, —OCHX¹⁰ ₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10), —NR^(10A)R^(10B), C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A) C(O)OR^(10C), —NR^(10A)OR^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹⁰ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(10A), R^(10B), R^(10C), and R^(10D) are independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(10A) and R^(16B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

X and X¹⁰ are independently —F, —Cl, —Br, or —I;

n10 is independently an integer from 0 to 4;

m10 and v10 are independently 1 or 2; and

z10 is an integer from 0 to 5.

Embodiment 5. The compound of one of embodiments 1 to 4 wherein L² is—C(R⁶)₂—.

Embodiment 6. The compound of one of embodiments 1 to 4 wherein L² is—CHR⁶—.

Embodiment 7. The compound of one of embodiments 1 to 4 wherein L² is abond.

Embodiment 8. The compound of one of embodiments 1 to 6 wherein R⁶ isunsubstituted alkyl.

Embodiment 9. The compound of one of embodiments 1 to 6 wherein R⁶ ishydrogen.

Embodiment 10. The compound of one of embodiments 1 to 9 wherein W¹ isNH.

Embodiment 11. The compound of one of embodiments 1 to 9 wherein W¹ isS.

Embodiment 12. The compound of one of embodiments 1 to 9 wherein W¹ isO.

Embodiment 13. The compound of one of embodiments 1 to 12 wherein W² isNH.

Embodiment 14. The compound of one of embodiments 1 to 12 wherein W² isS.

Embodiment 15. The compound of one of embodiments 1 to 12 wherein W² isO.

Embodiment 16. The compound of one of embodiments 1 to 15 wherein W¹ andR⁶ are joined to form a substituted or unsubstituted 5 to 6 memberedheterocycloalkyl or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 17. The compound of one of embodiments 1 to 15 wherein W¹ andR⁶ are joined to form a substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 18. The compound of one of embodiments 1 to 15 wherein W¹ andR⁶ are joined to form

Embodiment 19. The compound of one of embodiments 1 to 18 wherein R²,R⁴, R⁵, and R⁸ are hydrogen.

Embodiment 20. The compound of one of embodiments 1 to 19 wherein R³ issubstituted or unsubstituted C₁-C₆ alkyl.

Embodiment 21. The compound of one of embodiments 1 to 19 wherein R³ ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl.

Embodiment 22. The compound of one of embodiments 1 to 19 wherein —OR³is a prodrug moiety.

Embodiment 23. The compound of one of embodiments 1 to 19 wherein —OR³is a prodrug moiety capable of being cleaved from the remainder of thecompound by an esterase or amidase.

Embodiment 24. The compound of one of embodiments, 1 to 19 wherein R³ issubstituted or unsubstituted C₁-C₈ alkyl,

substituted or unsubstituted aryl, (acyloxy)alkyl,[(alkoxycarbonyl)oxy]methyl, or (oxodioxolyl)methyl.

Embodiment 25. The compound of one of embodiments 1 to 19 wherein R³ ishydrogen.

Embodiment 26. The compound of one of embodiments 1 to 25, wherein L^(l)is a bond.

Embodiment 27. The compound of one of embodiments 1 to 25, wherein L^(l)is —C(O)—.

Embodiment 28. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is unsubstituted C₁-C₆ alkyl.

Embodiment 29. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 30. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is substituted or unsubstituted cyclohexyl.

Embodiment 31. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is substituted or unsubstituted cyclohexyl, adamantyl,tetrahydronaphthyl, dihydroindenyl, or bicyclo[3 .3. 1]heptanyl , 2,3-dihydro-1H-indenyl .

Embodiment 32. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is substituted or unsubstituted C₇-C₁₂ fused cycloalkyl.

Embodiment 33. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is substituted or unsubstituted C₇-C₁₂ bridged cycloalkyl.

Embodiment 34. The compound of one of embodiments 1 and 3 to 27, whereinR⁷ is substituted or unsubstituted C₇-C₁₅ spirocyclic cycloalkyl.

Embodiment 35. The compound of one of embodiments 1 and 3 to 27, whereinwherein

wherein z21 is an integer from 0 to 5.

Embodiment 36. The compound of one of embodiments 1 and 3 to 27, whereinwherein

Embodiment 37. The compound of one of embodiments 2 to 27, wherein RingA is 5 to 6 membered heteroaryl.

Embodiment 38. The compound of one of embodiments 2 to 27, wherein RingA is phenyl.

Embodiment 39. The compound of one of embodiments 2 to 27, wherein RingA is a bicyclic C₉-C₁₀ aryl or bicyclic 8 to 10 membered heteroaryl.

Embodiment 40. The compound of one of embodiments 2 to 39, wherein z21is an integer from 1 to 5.

Embodiment 41. The compound of one of embodiments 2 to 39, wherein z21is 0.

Embodiment 42. The compound of one of embodiments 1 to 39, having theformula:

Embodiment 43. The compound of one of embodiments 1 to 39, having theformula:

Embodiment 44. The compound of one of embodiments 1 to 39, having theformula:

wherein R¹ is

Embodiment 45. The compound of embodiment 44, wherein

wherein z21 is an integer from 0 to 5;

wherein z21 is an integer from 0 to 4;

wherein R⁷ is substituted or unsubstituted cycloalkyl;

wherein z21 is an integer from 0 to 3;

wherein z21 is an integer from 0 to 2; or

wherein z21 is an integer from 1 to 5.

Embodiment 46. The compound of one of embodiments 1 to 39, having theformula:

wherein R¹ is

Embodiment 47. The compound of embodiment 46, wherein

wherein z21 is an integer from 0 to 5;

wherein z21 is an integer from 0 to 4;

wherein R⁷ is substituted or unsubstituted cycloalkyl;

wherein z21 is an integer from 0 to 3; or

wherein z21 is an integer from 0 to 2.

Embodiment 48. The compound of embodiment 1, having the formula:

Embodiment 49. A pharmaceutical composition comprising apharmaceutically acceptabR¹ excipient and a compound of one ofembodiments 1 to 48.

Embodiment 50. A method of treating asthma, the method comprisingadministering to a subject in need thereof an effective amount of anintegrin α2β1 inhibitor.

Embodiment 51. The method of embodiment 50, wherein the α2β1 inhibitoris a nucleic acid, protein, or compound.

Embodiment 52. The method of embodiment 50, wherein the α2β1 inhibitoris compound of one of embodiments 1 to 48.

Embodiment 53. A method of treating asthma, the method comprisingadministering to a subject in need thereof an effective amount of acompound of one of embodiments 1 to 48.

Embodiment 54. A method of treating asthma, the method comprisingadministering to a subject in need thereof an effective amount of acompound, or a pharmaceutically, having the formula:

wherein,

R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

L¹ is a bond or —C(O)—;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³,—OCHX³ ₂, —CN, —SO_(n3)R^(3D), —SO_(v3)NR^(3A)R^(3B),—NHC(O)NR^(3A)R^(3B), N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3C),—C(O)—OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D), —NR^(3A)SO₂R^(3D),—NR^(3A)C(O)R^(3C), —NR^(3A)C(O)OR^(3C)—NR^(3A)OR^(3C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

W¹ is O, S, NR⁸;

W² is O, S, NR^(S);

R⁵ is hydrogen or substituted or unsubstituted alkyl;

L² is a bond or —CHR⁶—;

R⁶ is hydrogen, ═NH, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl;

W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl;

R⁷ is hydrogen, halogen, —CX⁷ ₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷,—OCHX⁷ ₂, —CN, —SO_(n7)R^(7D), —SO_(v7)NR^(7A)R^(7B),—NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B), —C(O)R^(7C),—C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)OR^(7C), —NR^(7A)OR⁷, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;

R⁸ is hydrogen or substituted or unsubstituted alkyl;

R^(3A), R^(3B), R^(3C), R^(3D), R^(7A), R^(7B), R^(7C), and R^(7D) areindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

each X, X³, and X⁷ are independently —F, —Cl, —Br, or —I;

n3 and n7 are independently an integer from 0 to 3; and

m3, m7, v3 and v7 are independently 1 or 2.

Embodiment 55. The method of embodiment 54, wherein R¹ is

or substituted or unsubstituted C₄-C₈ alkyl;

wherein,

R⁹ is independently halogen, —CX⁹ ₃, —CHX⁹ ₂, —CH₂X⁹, —OCX⁹ ₃, —OCH₂X⁹,—OCHX⁹ ₂, —CN, —SO_(n9)R^(9D), —SO_(v9)NR^(9A)R^(9B),—NHC(O)NR^(9A)R^(9B), —N(O)m9,—NR^(9A)R^(9B), —C(O)R^(9C),—C(O)—OR^(9C), —C(O)NR^(9A)R^(9B)—OR^(9D), —NR^(9A)SO₂R^(9D),—NR^(9A)C(O)R^(9C)—NR^(9A)C(O)O R^(9C), —NR^(9A)OR^(9C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹⁰ is independently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH ₂X¹⁰ , —OCX¹⁰ ₃,—OCH₂X¹⁰ , —OCHX¹⁰ _(2,)—CN, —SO_(n10)R^(10 D),—SO_(v10)NR^(10A)R^(10B), —NHC(O)NR^(10A)R^(10B), —N(O)_(m10),—NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10C),—C(O)NR^(10A)R^(10B),—OR^(10D), 13 NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹⁰ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), and R^(10D)are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH ₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(9A) and R^(9B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(10A) and R^(10B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

X, X⁹, and X¹⁰ are independently —F, —Cl, —Br, or —I;

n9 and n10 are independently an integer from 0 to 4;

m9, m10, v9 and v10 are independently 1 or 2;

z9 is an integer from 0 to 5; and

z10 is an integer from 0 to 5.

Embodiment 56. The method of one of embodiments 54 to 55, wherein R¹ is

Embodiment 57. The method of one of embodiments 54 to 56, wherein the

compound is

Embodiment 58. The method of embodiment 54, wherein the compound is

Embodiment 59. The method of one of embodiments 54 to 56, wherein R⁷ issubstituted or unsubstituted cycl ° alkyl .

Embodiment 60. The method of one of embodiments 54 to 56, wherein R⁷ issubstituted or unsubstituted cyclohexyl, adamantly, tetrahydronaphthyl,dihydroindenyl, or bicyclo[3.3.1]heptanyl, 2,3—dihydro—1H—indenyl.

Embodiment 61. The method of one of embodiments 54 and 56, wherein

wherein z21 is an integer from 0 to 5.

Embodiment 62. The method of one of embodiments 54 and 56, wherein

Embodiment 63. The method of one of embodiments 54 to 56, wherein Ring Ais a bicyclic C₉-C₁₀ aryl or bicyclic 8 to 10 membered heteroaryl.

EXAMPLES

Inhibitors of Integrin α₂β₁ to Mitigate Smooth MuscR¹ Contraction inAsthma. Integrin α₂β₁ plays an important roR¹ in mediating adhesion ofairway smooth muscle cells to collagen, which is increased in the airwaywall of patients with asthma. We also found that blockade of thisintegrin inhibits cytokine-enhanced force generation in mouse trachealrings. Currently available inhibitors of integrin α₂β₁ are limited bypoor cell permeability and short in vivo half-life. Described herein isthe development of α₂β₁ inhibitors. Efforts will also focus oninhibitors optimized for oral or aerosol delivery. Such a drug could beused either alone or in conjunction with other currently availabletherapies to enhance smooth muscle relaxation in patients suffering fromsevere persistent asthma. Such an approach has the potential to benefitthe more than four million patients with severe asthma and persistentsymptoms despite maximal medical therapy and would be an importantaddition to the otherwise limited options for smooth-muscle targetedtherapy in acute exacerbations of asthma.

Described herein is research focused on therapeutically leveraging anindependently regulated alternate pathway used by smooth muscle cells totransmit the tension generated by an individual cell to the surroundingtissue via transmembrane integrins (10), which are bound intracellularlyto focal adhesion complexes and extracellularly to matrix proteins (11,12) . Previous work from our laboratory has shown that mice lacking theα_(v)β₆ integrin are protected from airway hyperreactivity, and thatthis effect is mediated in part by the effect of TGF-β on thesuppression of mouse mast cell protease-4 (mMCP-4) (13). Human mast cellchymase is the closest orthologue of mMCP-4, and has been suggested tobe protective against asthma severity in humans (14). Our lab has shownthat chymase protects against IL-13 enhanced contraction, and does sowithout modulating the classical actin-myosin contractile apparatus.Rather, chymase cleaves the extracellular matrix protein fibronectin toimpair tension transmission. Integrin α₅β₁ is the primary contributor tofibronectin-mediated adhesion, and blockade of α₅β₁ not onlyrecapitulates the protective effects of chymase, but actssynergistically with existing bronchodilators to enhance relaxation ofpre-contracted airways (15).

In addition to fibronectin, collagen is a well-established extracellularmatrix protein that is upregulated in the asthmatic airway. Of thecanonical collagen binding integrins (α₁β₁, α₂β₁, α₁₀β₁, and α₁₁β₁, wefound that α₂β₁ is highly expressed by human airway smooth muscle cells.In preliminary studies that form the basis for this proposal, we havefound that blockade of integrin α₂β₁ inhibits adhesion to collagen, andis protective against the development of airway hyperresponsiveness exvivo and in vivo. Additionally, it enhances isoproterenol-inducedrelaxation, establishing its efficacy as an important adjunctive agentto aid in smooth muscle relaxation. Of note, integrin α₂β₁ deficientmice have no hemostatic defects, and human deficiencies of integrin α₂β₁result in only a mild bleeding diathesis. In vitro, inhibition of α₂β₁has also been described to result in decreased thrombus formation onlyon type I collagen, suggesting that this integrin is only a secondarymediator of microvascular thrombosis. We anticipate that blockade ofthis integrin will not result in significant vascular side effects.Targeting cell-matrix interactions via blockade of integrin α₂β₁ toimpair tension transmission is a novel therapeutic strategy forbronchoconstriction. Currently available inhibitors of integrin α₂β₁ arelimited by poor cell permeability and short in vivo half-life, and thereis room for development of novel inhibitors that could be used for oralor inhaled therapy, either alone or as an adjunctive agent, with thegoal of reducing the need for other asthmatic medications that carrymore significant side effects (eg. corticosteroids).

The contribution of integrin-mediated matrix associations to smoothmuscle force generation in asthma is a novel idea. This therapeuticstrategy was validated with blockade of integrin a5f3i association withfibronectin, with measurable decreases in airway contraction in both exvivo and in vivo models of disease. Based on the preliminary data thatblockade of integrin α₂β₁ protects against airway contraction in both invivo and ex vivo models of disease, and the pharmacologic limitations ofcurrently available inhibitors, described herein are efforts to designand synthesize novel small molecule inhibitors of integrin α₂β₁ withimproved pharmacokinetic and pharmacodynamics properties and validatetheir therapeutic efficacy in a mouse model of asthma.

Described herein is the synthesis of candidate compounds, followed by acombination of cell-based screening, ex vivo contraction assays, PKassessments, and in vivo responses to allergen sensitization andchallenge to identify a lead compound that is a potent and specificinhibitor of integrin α₂β₁. This compound will be designed with the goalof being used via oral or inhalational routes, either alone or incombination with other currently available bronchodilator therapy, toreduce force transmission by airway smooth muscle to relieve pathologicairway narrowing.

Disruption of cell tethering to the matrix via selective integrinblockade has functional consequences on force generation in smoothmuscle. We showed that inhibition of integrin α5β1, the majorfibronectin receptor on airway smooth muscle, not only inhibitsIL-13-mediated enhanced force generation by mouse tracheal and humanbronchial rings, but also inhibits airway hyperresponsiveness in a mousemodel of asthma (FIG. 1A). Furthermore, targeting integrin-mediated celltethering (and consequently force transmission) results in additiverelaxation responses to currently available bronchodilator therapy (FIG.1B) (15).

Collagen is a matrix protein that is upregulated in the asthmaticairway, so we reasoned that integrins participating in collagen-mediatedadhesion may also play a role in tension transmission. We performed aqRT-PCR screen to identify integrins present in human airway smoothmuscle. Of the canonical collagen binding integrins (α₁β₁, α₂β₁, α₁₀β₁,and α₁₁β₁), integrin α₂β₁ is highly expressed in airway smooth muscle.Blockade of integrin α₂α₁ inhibits adhesion to collagen in vitro (FIG.2A) and also protects against IL-13 enhanced contraction ex vivo (FIG.2B). We therefore investigated the effect of inhibition of integrinα_(a)β₁ in vivo and found that mice were protected from the developmentof airway hyperresponsiveness in a mouse model of asthma (FIG. 3A),using our inhibitor, C15, which has an in vitro IC50 of ˜2 μM (FIG. 3B).Currently available inhibitors of integrin α₂β₁ are limited by poor cellpermeability, only modest potency, and short half-life, thus laying thegroundwork for the experiments that follow.

The first small molecule inhibitors of integrin α₂β₁, including compound9 (C9) (16) (FIG. 3) C9 showed a nanomolar potency (IC₅₀=15 nM) inplatelet adhesion assays and good selectivity over integrins α₄β₁ andα₅β₁. Subsequently, others reported the cyclic peptide compound 38 (17)as another integrin α₂β₁ inhibitor, which also contains theamidocarboxylic acid with C9. Unfortunately, compound 38 suffered fromlow cellular permeability. We also discovered that modification of theN-benzenesulfonyl thiazolidine moiety in C₉ and C15 (18) greatlyimproved in vivo efficacy in a mouse model of renal fibrosis (19).However, C15 was administered by intraperitoneal (IP) injection.

We are developing a second generation of integrin α₂β₁ inhibitors withimproved drug-like properties. We are modifying C15 to increase oralavailability at multipR¹ sites (FIG. 5). The phenylsulfonyl-thiazolidinederivative adds both peptidic character and increases both the polarityand the MW (the heavy atom count of this moiety is 19 in c15) of theinhibitor. Through extensive SARs of other integrin β₁ inhibitors (20,21, 22) we found that this group can be substituted by 2,6-disubstitutedphenylamide, certain alkyl amides or substituted pyrimidines. Indeed, werecently synthesized an analogue A2-4 with a much smaller R₁ group (halfthe heavy atom count of R₁ in c15) which was only 2-fold less potent ina cell adhesion assay.

Thus, a focused effort at optimizing the Ri substituent will besuccessful. These moieties could be easily installed on the commonintermediate to facilitate compound synthesis. Improved potency andlipophilicity will be also pursued by replacing the urea (R2) withdiverse heterocycles, and adding substituents to the terminal aryl ring.Virtual docking will be used to interpret SAR and to prioritizemolecules for synthesis and prodrugs of the acid are being explored.

i. Synthesis and Characterization Data of the Compounds

LC-MS condition A: AB Sciex 3200 LC/MS/MS with Shimadzu HPLC System,Column: ACEUltraCore 2.5 SuperC18 (2.1×50 mm) buffer A: 0.1% TFA in H20,buffer B: 0.1% TFA in acetonitrile-H₂O (99:1). Flow rate: 0.4 mL/min,gradient 5 to 100% B over 3 min.

LC-MS condition B: AB Sciex 3200 LC/MS/MS with Shimadzu HPLC System,Column: ACEUltraCore 2.5 SuperC18 (2.1×50 mm) buffer A: 0.1% TFA in H20,buffer B: 0.1% TFA in 2-propanol-acetonitrile-H₂O (60:30:10). Flow rate:0.6 mL/min, gradient 5 to 100% B over 2 min

LC-MS condition C: AB Sciex 3200 LC/MS/MS with Shimadzu HPLC System,Column: Agilent poroshell 120, EC-C₈ (2.1×50 mm) buffer A: 0.1% TFA inH₂O, buffer B: 0.1% TFA in acetonitriR¹. Flow rate: 0.4 mL/min, gradient0 to 100% B over 3 min.

LC-MS condition D: AB Sciex 3200 LC/MS/MS with Shimadzu HPLC System,Column: ACEUltraCore 2.5 SuperC18 (2.1×50 mm) buffer A: 0.1% TFA in H20,buffer B: 0.1% TFA in 2-propanol-acetonitrile-H₂O (60:30:10). Flow rate:0.4 mL/min, gradient 5 to 100% B over 2 min

Analytical HPLC condition A: Column Jupiter, 5 μm, C4, 300 Å, 4.6 mmi.d. ×250 mm, buffer A: 0.1% TFA in H20, buffer B: 0.1% TFA inacetonitriR¹-H20 (99:1). Flow rate: 1 mL/min, a gradient of 5-100% Bover 40 min

To a solution of Boc-DAP-OMe (lmmol) in DMF (3mL) was added DIPEA (4eq.) followed by 2,6-dichlorobenzoic acid (1.3 eq.) and HCTU (0.95 eq).at rt. The mixture was stirred for 2 h and diluted with ethyl acetate.The organic layer was washed with 1M hydrochloric acid, Sat. NaHCO3, andbrine successively and concentrated under vacuo. The crude residue waspurified by flash column chromatography (DCM:MeOH=100:0 to 95:5) toyield the product (240mg). MS (ESI, positive)=413.4(MNa⁺). The productwas treated with 4M HCl in dioxane (3mL) for 2h at rt and concentrated.The crude residue was triturated with diethyl ether to yield the amine(130 mg). The amine (0.2 mmol) was dissolved inn DCM (3mL) and DIPEA(Seq.) was added at rt. To the mixture was added benzyl isocyanate (5eq.). The mixture was stirred overnight and concentrated. The crudemixture was purified by flash column chromatography (DCM:MeOH=100:0 to90:10). The ester was dissolved in THF:H₂O (4:1, 5mL) and treated with1M LiOH (0.5 mL) for 2h. The mixture was acidified to pH=2 andconcentrated and purified RP-HPLC. MS (ESI, positive)=410.5 (MH⁺).

(S)-3-(3-benzylureido)-2-(2,6-dichlorobenzamido)propanoic acid (A2-4):¹H NMR (300 MHz,CDCl₃+CD3OD) δ ppm 7.36-7.27 (m, 8H), 4.7 (br s, 1H),4.32-4.3 (m, 2H), 3.7 (br s, 2H). LC-MS (condition A) m/z=410.5 (MEI⁺),Retention time=4.93 min.

(S)-2-(2,6-di chl orob enzami do)-3-(3-(naphthal en-l-yl)urei do)propanoi c acid (A2-189) Prepared from 1-naphthylisocyanate according to theprocedure for A2-4. ¹H NMR (300 MHz, CDCl₃₊CD₃OD) δ ppm 7.99 (d, J=7.5Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.72-7.63 (m, 2H), 7.54-7.25 (m, 6H),4.74 (br s, 1H), 3.90-3.70 (m, 2H). LC-MS (condition B) m/z=446.4 (ME⁺),Retention time=2.00 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(naphthalen-2-yl)ureido)propanoicacid (A2-190) Prepared from 2-naphthylisocyanate according to theprocedure for A2-4. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.90 (br s, 1H),7.75-7.68 (m, 3H), 7.44-7.20 (m, 6H), 4.81-4.77 (m, 1H), 3.89-3.71 (m,2H). LC-MS (condition B) m/z=446.4 (MH⁺), Retention time=2.00 min.

Synthesis of A2-26

To a solution of Boc-DAP-OMe (2mmo1) in DMF (8mL) was added DIPEA (2.3eq.) followed by 2,6-dichlorobenzoic acid (1 eq) and HATU (0.95 eq). atrt. The mixture was stirred for 2 h and diluted with ethyl acetate. Theorganic layer was washed with 1M hydrochloric acid, Sat. NaHCO₃, andbrine successively and concentrated under vacuo. The crude product wastreated with 4M HCl in dioxane (8 mL) for 3h at rt and concentrated. Thecrude residue was triturated with diethyl ether and the solid wasisolated and dried in vacuo. To the crude amine HCl salt (100mg, 0.3mmol) was dissolved in DCM (3mL) and Et3N (5eq) was added at rt. To themixture was added benzyl isocyanate (2 eq). The mixture was stirredovernight and the organic layer was washed with 0.5 M HCl followed bysat. NaHCO₃ solution. The mixture was dried over Na₂SO₄ and concentratedin vacuo. The crude mixture was dissolved in THF:H₂O (4:1, 5mL) andtreated with 1M LiOH (0.3 mL) for 2h. The mixture was acidified to pH=2and purified by RP-HPLC to provide A2-26.

(S)-3-(3-benzylureido)-2-(2,4,6-trimethylbenzamido)propanoic acid(A2-26): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.28-7.18 (m, 5H), 6.78 (s,2H), 4.63-4.59 (m, 1H), 4.24 (s, 2H), 3.64-3.6 (m, 2H). LC-MS (conditionA) m/z=384.7 (MW), Retention time =5.27 min

(S)-3-(3-benzylureido)-2-(2,6-bis(trifluoromethyl)benzamido)propanoicacid (A2-27): Prepared from 2,6-ditrfluoromethylbenzoic acid accordingto the procedure for A2-26. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm7.94-7.91 (d, J=8.1 Hz, 2H), 7.69 (t, J=8.4 Hz, 1H), 7.33-7.26 (m, 5H),4.59 (t, J=4.2Hz, 1H), 4.24 (s, 2H), 3.76-3.55 (m, 2H). LC-MS (conditionA) m/z=478.5 (MH⁺), Retention time=5.25 min

(S)-3-(3-benzylureido)-2-(2,6-dimethoxybenzamido)propanoic acid (A2-28):Prepared from 2,6-dimethoxybenzoic acid according to the procedure forA2-26. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.32-7.22 (m, 6H), 6.56 (d,J=8.4Hz, 2H), 4.67 (t, J=4.5Hz, 1H), 4.32 (s, 2H), 3.77 (s, 6H),3.76-3.6 (m, 1H), 3.58-3.52 (m, 1H). LC-MS (condition A) m/z=402.5(MH⁺), Retention time=4.69 min

(S)-3-(3-benzylureido)-2-(3,5-dichloroisonicotinamido)propanoic acid(A2-29) Prepared from 3,5-dichloropyridine-4-carboxylic acid accordingto the procedure for A2-26. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 8.52 (s,2H), 7.30-7.22 (m, 5H), 4.71 (t, J=6Hz, 1H), 4.36-4.22 (m, 2H),3.72-3.66 (m, 2H). LC-MS (condition A) m/z=411.6 (MH⁺), Retentiontime=4.60 min

(S)-3-(3-benzylureido)-2-(2-chloro-6-methylbenzamido)propanoic acid(A2-35) Prepared from 2-chloro-6-methylbenzoic acid according to theprocedure for A2-26. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.32-7.15 (m,7H), 7.09-7.06 (m, 1H),4.64 (m, 1H), 4.27 (s, 2H), 3.74-3.58 (m, 2H),2.31 (s, 3H). LC-MS (condition A) m/z=390.5 (MH+), Retention time=5.00min

(S)-3-(3-benzylureido)-2-(2-bromo-6-fluorobenzamido)propanoic acid(A2-36): Prepared from 2-bromo-6-fluorobenzoic acid according to theprocedure for A2-26. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.37(d,J=8.1Hz,1H), 7.30-7.18 (m, 6H), 7.07 (t, J=8.4Hz, 1H), 4.66 (t, J=5.1Hz,1H), 4.30 (s, 2H), 3.72-3.6 (m, 2H). LC-MS (condition A) m/z=438.4(MH⁺), Retention time=4.92 min

(S)-3-(3-benzylureido)-2-(3-methylbutanamido)propanoic acid (A2-37):Prepared from 3-methylbutanic acid according to the procedure for A2-26.¹H NMR (300

MHz, CDCl₃+CD₃OD) δ ppm 7.33-7.2 (m, 5H), 4.46-4.43 (m, 1H), 4.32 (s,2H), 3.57 (d, J=5.7Hz, 2H), 2.11-2.07 (m, 3H), 0.94-0.92 (s, 6H). LC-MS(condition A) m/z=322.7 (MH⁺), Retention time=4.65 min

(S)-3-(3-benzylureido)-2-(2-ethylbutanamido)propanoic acid (A2-38):Prepared from 2-ethylbutanic acid according to the procedure for A2-26.^(I)E NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.3-7.18 (m, 5H), 4.45-4.40 (m,1H), 4.38-4.25 (m, 2H), 3.57-3.52 (m, 2H), 2.00-1.98 (m, 1H), 1.60-1.43(m, 4H), 11-2.07 (m, 3H), 0.91-0.80 (m, 6H). LC-MS (condition A)m/z=336.5 (MH⁺), Retention time=4.87 min

(S)-3-(3-benzylureido)-2-(4-methoxy-2,6-dimethylbenzamido)propanoic acid(A2-60): Prepared from 4-methoxy-2,4-dimethylbenzoic acid according tothe procedure for A2-26. ^(I)H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm7.30-7.18 (m, 5H), 6.51 (s, 2H), 4.62-4.59 (m, 1H), 4.25 (s, 2H), 3.76(s, 3H), 3.64-3.61 (m, 2H), 2.25 (s, 6H). LC-MS (condition A) m/z=400.6(MH⁺), Retention time=5.00 min

(S)-3-(3-benzylureido)-2-(4-isopropoxy-2,6-dimethylbenzamido)propanoicacid (A2-61): Prepared from 4-isopropoxy-2,4-dimethylbenzoic acidaccording to the procedure for A2-26. ^(I)H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.30-7.18 (m, 5H), 6.52 (s, 2H), 4.64-4.59 (m, 1H), 4.5-4.45 (m,1H), 4.27 (s, 2H), 3.64-3.62 (m, 2H), 2.25 (s, 6H), 1.30 (d, J=5.7 Hz,6H). LC-MS (condition A) m/z=428.6 (MH³⁰), Retention time=5.53 min.

(S)-3-(3-benzylureido)-2-(cyclohexanecarboxamido)propanoic acid (A2-63):Prepared from cyclohexane carboxylic acid according to the procedure forA2-26. ¹H NMR (300 MHz, CDC13+CD30D) δ ppm 7.33-7.22 (m, 5H), 4.38-4.37(m, 1H), 4.32 (s, 2H), 3.63-3.47 (m, 2H), 2.14 (m,1H), 1.4-1.2 (m, 5H).LC-MS (condition A) m/z=348.5 (MH⁺), Retention time=4.97 min.

(S)-3-(3-benzylureido)-2-(2-cyclohexylacetamido)propanoic acid (A2-64):Prepared from cyclohexyl acetic acid according to the procedure forA2-26. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.33-7.22 (m, 5H), 4.5-4.37(m, 3H), 3.62-3.49 (m, 2H), 2.12-2.08 (m, 2H),1.72-1.65 (m, 6H), 1.3-0.8(m, 5H). LC-MS (condition A) m/z=379.6 (MH⁺), Retention time=5.62 min.

Synthesis of A2-39

To a solution of Boc-DAP-OMe (0.39 mmol) in DMF (2mL) was added asolution of DIPEA (4 eq.), 2,6-dichlorobenzoic acid (1.0 eq.) and HCTU(0.95 eq). at rt. The mixture was stirred for 2 h and diluted with ethylacetate. The organic layer was washed with water and brine successivelyand dried over Na2SO4. The mixture was concentrated under vacuo and wasdissolved in THF-H₂O(3:1, 4mL). LiOH solution (1M, 900 uL) was added andstirred for 2h. The solution was neutralized by HCl solution to pH=7 andlyophilized. Final product was purified by RP-HPLC to yield the product.

(S)-3-((tert-butoxycarbonyl)amino)-2-(2,6-dichlorobenzamido)propanoicacid (A2-39): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.36-7.25 (m, 5H),4.76 (br s, 1H), 3.72-3.60 (m, 2H), 1.42 (s, 9H). LC-MS (condition A)m/z=377.4 (MH⁺), Retention time =5.19 min.

Synthesis of A2-70

To a solution of INT-1 (0.34 mmol) and DIPEA (3eq) in DCM (4mL) wasadded dimethylcarbamoyl chloride (1.5eq) at rt and stirred for 2h. Thenadditional DIPEA (200 uL) and dimethylcarbamoyl chloride (1.5 eq) wasadded and stirred overnight. The solution was washed with 1M HClsolution and Sat. NaHCO₃ solution successively and concentrated underreduced pressure. The crude mixture was dissolved in THF:H₂O (4:1, 5 mL)and treated with 1M LiOH (0.6 mL) for 2h. The mixture was acidified topH=2 and purified by RP-HPLC to provide A2-70.

(S)-2-(2,6-dichlorobenzamido)-3-(3,3-dimethylureido)propanoic acid(A2-70): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.36-7.25 (m, 3H),4.73-4.69 (m, 1H), 3.81-3.61 (m, 2H), 2.89 (s, 6H). LC-MS (condition A)m/z=348.3 (MH⁺), Retention time=4.15 min

(S)-2-(2,6-dichlorobenzamido)-3-(3,3-diethylureido)propanoic acid(A2-71): Prepared from diethylcarbamoyl chloride according to theprocedure for A2-70. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.36-7.25 (m,3H), 4.68-4.64 (m, 1H), 3.84-3.61 (m, 2H), 3.29-3.22 (m, 4H), 1.14 (t,J=6.9 Hz, 6H) LC-MS (condition A) m/z=376.3 (MH⁺), Retention time=4.69min.

Synthesis of A2-72

To a solution of INT-1 (0.34 mmol) and DIPEA (3eq) in DCM (4mL) wasadded dimethylcarbamoyl chloride (1.5eq) at rt and stirred for 2h. Thesolution was washed with 1M HCl solution and Sat. NaHCO₃ solutionsuccessively and concentrated under reduced pressure. The crude mixturewas dissolved in THF:H₂H(4:1, 5 mL) and treated with 1M LiOH (0.6 mL)for 2h. The mixture was acidified to pH=2 and purified by RP-HPLC toprovide A2-72.

(S)-3-(((benzyloxy)carbonyl)amino)-2-(2,6-dichlorobenzamido)propanoicacid

(A2-72): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.36-7.25 (m, 8H),5.12-5.02 (m, 2H), 4.83-4.81 (m, 1H), 3.75-3.73 (m, 2H), 3.29-3.22 (m,4H), 1.14 (t, J=6.9 Hz, 6H). LC-MS (condition A) m/z=411.4 (MH⁺),Retention time=5.37 min.

Synthesis of A2-73

To a solution of INT-1 (0.34 mmol) and DIPEA (3eq) in DMF (4mL) wasadded 2-chloro-4-phenylpyrimidine (1.5eq) at rt and stirred for 2h at85° C. After cool to rt, another portion of DIPEA (3eq) and2-chloro-4-phenylpyrimidine (1.5eq) were added and stirred for 3h at 85°C. After cooling to rt, the reaction mixture was diluted with ethylacetate and washed with 1M HCl solution and Sat. NaHCO3 solutionsuccessively and concentrated under reduced pressure. The crude mixturewas dissolved in THF:H₂O (4:1, 5 mL) and treated with 1M LiOH (0.6 mL)for 2h. The mixture was acidified to pH=2 and purified by RP-HPLC toprovide A2-73.

(S)-2-(2,6-dichlorobenzamido)-3-((4-phenylpyrimidin-2-yl)amino)propanoicacid (A2-73): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 8.22-8.15 (m, 3H),7.64-7.52 (m, 3H), 7.3-7.2 (m, 4H), 5.2-5.1 (m, 1H), 4.4-4.3 (m, 1H),4.1-4.05 (m, 1H). LC-MS (condition A) m/z=431.3 (MH⁺), Retentiontime=5.28 min.

Synthesis A2-87

To a solution of INT-1 (0.34 mmol) and DIPEA (3eq) in DMF (3mL) wasadded amantadine isocyante (1eq) and stirred overnight at rt. Thereaction mixture was diluted with ethyl acetate and washed with 0.5 MHCl solution and Sat. NaHCO3 solution successively and concentratedunder reduced pressure. The crude mixture was purified by columnchromatography (0% to 10% MeOH in DCM)(ESI-MS: 468.6 (MH+)). Th esterwas dissolved in THF:H₂O (4:1, 4 mL) and treated with 1M LiOH (0.5 mL)for 2h. The mixture was acidified to pH=2 and purified by RP-HPLC toprovide A2-87.

(S)-3-(((3R,5R,7R)-adamantan-1-yl)amino)-2-(2,6-dichlorobenzamido)propanoicacid (A2-87): ¹NMR (300 MHz, CDCl₃+CD₃OD) δ 8.22-8.15 (m, 3H), 7.64-7.52(m, 3H), 7.3-7.2 (m, 4H), 5.2-5.1 (m, 1H), 4.4-4.3 (m, 1H), 4.1-4.05 (m,1H). LC-MS (condition A) m/z=431.3 (MH⁺), Retention time=5.28 min.

Synthesis of A2-83

To a stirred solution of aminomethyladamantane (1 mmol) and pyridine(1.5 eq) in anhydrous DCM (4mL) was added p-nitrophenylchloroformate (1eq) at 0° C. The mixture was warmed to rt and stirred for 4h. Themixture was concentrated under reduced pressure and filtered through ashort pad of silica (washed with 0 to100% ethyl acetate in hexanes) toseparate the p-nitrophenylcarbamate product which was dissolved inanhydrous DMF (3mL). To this mixture was added a solution of INT-1 (0.3mmol) and Et₃N (1 mmol) in DMT (1 mL) at rt. The mixture was stirredovernight and diluted with ethyl acetate. The organic layer was washedwith 0.5 M HCl solution (5 mL), sat. NaHCO₃ (6 mL) and brine,successively. After concentration under reduced pressure, the crudeester was purified by silica gel column chromatography (Eluant: 0 to 15%MeOH in DCM). (ESI-MS: 482.5 (MH⁺). The ester was dissolved in THF:H₂O(4:1, 3 mL) and treated with 1M LiOH (0.22 mL) for 2h. The mixture wasacidified to pH=2 and purified by RP-HPLC to provide A2-83.

(2S)-3-(3-(((1s,3R)-adamantan-1-yOmethypureido)-2-(2,6-dichlorobernzamido)propanoicacid (A2-83): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ 7.34-7.26 (m, 3H),4.62-4.59 (m, 1H), 3.67-3.51 (m, 2H), 2.04 (s, 3H), 1.90 (s, 6H), 1.64(s, 6H). LC-MS (condition B) m/z=454.4 (MH⁺), Retention time=2.59 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(1,2,3,4-tetrahydronaphthalen-1-yl)ureido)propanoicacid (A2-124): Prepared from 1,2,3,4-tetrahydronaphthalen-1-amineaccording to the procedure for A2-83. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.35-7.26 (m, 4H), 7.16-7.02 (m, 2H), 4.87 (s, 1H), 4.65 (s, 1H),3.80-3.60 (m, 2H), 2.69 (m, 2H), 2.00-1.95 (m, 1H), 1.79 (m, 3H). LC-MS(condition B) m/z=450.3 (MH⁺), Retention time=2.43 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)propanoic acid (A2-125): Prepared from(S)-1,2,3,4-tetrahydronaphthalen-1-amine according to the procedure forA2-83. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ 7.35-7.26 (m, 4H), 7.16-7.02 (m,2H), 4.87 (s, 1H), 4.69-4.66(m, 1H), 3.80-3.60 (m, 2H), 2.8-2.62 (m,2H), 2.00-1.96 (m, 1H), 1.79 (m, 3H). LC-MS (condition B) m/z=450.4(MH⁺), Retention time=2.44 min

A2-126 was similarly prepared using 1,2,3,4-tetrahydronaphthalen-1-amineinstead of aminomethyladamantane.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(1,2,3,4-tetrahydronaphthalen-2-yl)ureido)propanoic acid (A2-126): Prepared from(S)-1,2,3,4-tetrahydronaphthalen- 1-amine according to the procedure forA2-83. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ 7.35-7.25 (m, 4H), 7.16-7.2 (m,2H), 4.68-4.65 (m, 1H), 4.00-3.97 (m, 1H), 3.68 (br s, 2H), 3.1-3,0(m,1H), 2.66-2.58 (m, 1H), 2.05-1.95 (m, 1H), 1.74-1.71 (m, 1H). LC-MS(condition B) m/z=450.3 (MH⁺), Retention time=2.45 min.

(S)-3-(3-benzhydrylureido)-2-(2,6-dichlorobenzamido)propanoic acid(A2-127): Prepared from diphenylmethanamine according to the procedurefor A2-83. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.61-7.35 (m, 13H), 5.94(br s, 1H), 4.66-4.63 (m, 1H), 3.69-3.68 (m, 2H), 3.1-3.0(m, 1H),2.66-2.58 (m, 1H), 2.05-1.95 (m, 1H), 1.74-1.71 (m, 1H). LC-MS(condition B) m/z=486.1 (MI-1⁺), Retention time=2.50 min.

(S)-3-(3-((adamantan-1-yl)methyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-133): Prepared from (adamantan-l-yl)methanamine according tothe procedure for A2-83. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.35-7.27(m, 3H), 4.66-4.63 (m, 1H), 3.70-3.64 (m, 2H), 3.26-3.22 (m, 2H),1.89-1.70 (m, 13H), 1.53-1.49 (m, 2H). LC-MS (condition B) m/z=468.4(MI-1⁺), Retention time=2.67 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3-hydroxyadamantan-1-yl)ureido)propanoicacid (A2-144): Prepared from 3-aminoadamantan-1-ol according to theprocedure for A2-83. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.33-7.25 (m,3H), 4.65-4.60 (m, 1H), 3.65-3.55 (m, 2H), 2.23 (br s, 2H), 1.88-1.75(m, 4H), 1.65 (br s, 3H), 1.52 (br s, 2H), 1.25-1.18 (m, 3H). LC-MS(condition B) m/z=470.2 (MH⁺), Retention time=1.94 min.

Synthesis of A2-84

To a stirred solution of 2,3-dihydro-1H-inden-2-amine HCl salt (1 mmol)and Et₃N (1 eq) and pyridine (1.5 eq) in anhydrous DCM (4mL) was addedp-nitrophenylchloroformate (1 eq) at 0° C. The mixture was warmed to rtand stirred for 4h. The mixture was concentrated under reduced pressureand filtered through a short pad of silica (washed with 0 to100% ethylacetate in hexanes) to separate the p-nitrophenylcarbamate product whichwas dissolved in anhydrous DMF (3mL). To this mixture was added asolution of INT-1 (0.25 mmol) and Et₃N (0.75 mmol) in DMF (1 mL) at rt.The mixture was stirred overnight and diluted with ethyl acetate. Theorganic layer was washed with 0.5 M HCl solution (5 mL), sat. NaHCO₃ (6mL) and brine, successively. After concentration under reduced pressure,the crude ester was purified by silica gel column chromatography(Eluant: 0 to 15% MeOH in DCM). (ESI-MS: 450.4 (MH⁺). The ester wasdissolved in THF:H₂O (4:1, 3 mL) and treated with 1M LiOH (0.22 mL) for2h. The mixture was acidified to pH=2 and purified by RP-HPLC to provideA2-84.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(2,3-dihydro-1H-inden-2-yl)ureido)propanoicacid (A2-84): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.35-7.26 (m, 3H),7.22-7.13 (m, 4H), 4.67-4.64 (m, 1H), 4.47-4.43 (m, 1H), 3.67-3.65 (m,2H), 3.33-3.18 (m, 2H), 2.79-2.72 (m, 2H). LC-MS (condition B) m/z=436.4(MH⁺), Retention time=2.38 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-((R)-2,3-dihydro-1H-inden-1-yl)ureido)propanoicacid (A2-85): Prepared from (R)-2,3-dihydro-1H-inden-1-amine HCl saltaccording to the procedure for A2-84. ¹⁻EINMR (300 MHz, CDCl₃+CD₃OD) δppm 7.35-7.15 (m, 7H), 5.21-5.16 (m, 1H), 4.72-4.68 (m, 1H), 3.72 (d,J=5.2 Hz, 2H), 2.97-2.75 (m, 2H), 67-4.64 (m, 1H), 4.47-4.43 (m, 1H),3.67-3.65 (m, 2H), 3.33-3.18 (m, 2H), 2.79-2.72 (m, 2H), 2.54-2.48 (m,1H), 1.8-1.7 (m, 1H). LC-MS (condition B) m/z=436.4 (MH⁺),

Retention time=2.00 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-((S)-2,3-dihydro-1H-inden-1-yl)ureido)propanoicacid (A2-86): Prepared from (S)-2,3-dihydro-1H-inden-1-amine HCl saltaccording to the procedure for A2-84. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.35-7.15 (m, 7H), 5.17 (t, J=7.35, 1H), 4.70-4.67 (m, 1H), 3.71 (d,J=5.2 Hz, 2H), 2.96-2.74 (m, 2H), 2.53-2.48 (m, 1H), 1.78-1.74 (m, 1H).LC-MS (condition B) m/z=436.4 (MH⁺), Retention time=2.26 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-((2,3-dihydro-1H-inden-1-yl)methyl)ureido)propanoicacid) (A2-123): Prepared from (2,3-dihydro-1H-inden-1-yl)methanamineyl)methanamine HCl salt according to the procedure for A2-84. ¹H NMR(300 MHz, CDCl₃+CD₃OD) δ ppm 7.3-7.15 (m, 7H), 4.65-4.64 (m, 1H),3.78-3.6 (m, 2H), 3.59-3.17 (m, 3H), 2.94-2.74 (m, 1H), 2.26-2.20 (m,1H), 1.83-1.77 (m, 1H). LC-MS (condition B) m/z=450.4 (MH⁺), Retentiontime=2.45 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3,5-dimethyladamantan-1-yl)ureido)propanoicacid (A2-128): Prepared from 3,5-dimethyladamantan-l-amine HCl saltaccording to the procedure for A2-84. ¹EINMR (300 MHz, CDCl₃+CD₃OD) δppm 7.35-7.26 (m, 3H), 4.61-4.57 (m, 1H), 3.61-3.58 (m, 2H), 2.14-2.05(m, 1H), 1.73 (br s, 1H), 1.58-1.54 (m, 4H), 1.36-1.24 (m, 4H), 1.12 (brs, 2H), 0.82 (s, 6H). LC-MS (condition B) m/z=482.4 (MH⁺), Retentiontime=2.75 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3-ethyladamantan-1-yl)ureido)propanoicacid (A2-129): Prepared from 3-ethyladamantan-l-amine HCl salt accordingto the procedure for A2-84. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm7.35-7.26 (m, 3H), 4.61-4.57 (m, 1H), 3.69-3.50 (m, 2H), 2.09 (br s,2H), 1.83 (br s, 4H), 1.60-1.50 (m, 4H), 1.37 (br s, 4H), 1.17-1.12 (m,2H), 0.80-0.75 (t, J=7.3Hz, 3H). LC-MS (condition B) m/z=482.3 (MH⁺),Retention time=2.75 min.

(S)-3-(3-(adamantan-2-yl)ureido)-2-(2,6-dichlorobenzamido)propanoic acid(A2-130): Prepared from adamantan-2-amine HCl salt according to theprocedure for A2-84. ¹H NIVIR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.35-7.26 (m,3H), 4.69-4.65 (m, 1H), 3.73-3.66 (m, 3H), 1.81-1.55 (m, 14H). LC-MS(condition B) m/z=454.3 (MH⁺), Retention time=2.59 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3-(trifluoromethyl)adamantan-1-yl)ureido)propanoicacid (A2-131): Prepared from 3-(trifluoromethypadamantan-1-amine HClsalt according to the procedure for A2-84. ¹H NMR (300 MHz, CDCl₃+CD₃OD)δ 7.35-7.26 (m, 3H), 4.61-4.57 (m, 1H), 3.67-3.52 (m, 2H), 1.98-1.85 (m,4H), 1.81-1.56 (m, 8H). LC-MS (condition B) m/z=522.3 (MH⁺), Retentiontime=2.65 min.

(2S)-3-(3-(1-(adamantan-1-yl)ethyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-132): Prepared from 1-(adamantan-l-yl)ethan-1-amine HCl saltaccording to the procedure for A2-84. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.36-7.26 (m, 3H), 4.63-4.60 (m, 1H), 3.78-3.52 (m, 2H), 3.41-3.35(m, 1H), 1.97 (br s, 3H), 1.72-1.4 (m, 12H), 1.01-0.98 (m, 3H). LC-MS(condition B) m/z=482.4 (WO, Retention time=2.70 min.

(S)-3-(3-(2-((adamantan-1-yl)ethyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-134): Prepared from 2-((adamantan-1-yl) ethan-1-amine HCl saltaccording to the procedure for A2-84. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.36-7.26 (m, 3H), 4.67-4.63 (m, 1H), 3.67-3.66 (m, 2H), 3.12-3.08(m, 2H), 1.90-1.48 (m, 17H). LC-MS (condition B) m/z=482.4 (MH⁺),Retention time=2.73 min.

3-(3-((S)-2-carboxy-2-(2,6-dichlorobenzamido)ethyl)ureido)adamantane-1-carboxylicacid (A2-143): Prepared from methyl 3-aminoadamantane-1-carboxylate HClsalt according to the procedure for A2-84. ¹H NMR (300 MHz, CDCl₃+CD₃OD)δ ppm 7.34-7.25 (m, 3H), 4.61-4.59 (m, 1H), 3.65-3.53 (m, 2H), 2.16 (brs, 2H), 2.03 (br s, 2H), 1.89 (br s, 4H), 1.8 (br s, 4H), 1.62 (br s,2H). LC-MS (condition B) m/z=498.5 (MEr), Retention time=1.87 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(hexahydro-2,5-methanopentalen-3a(1H)-yl)ureido)propanoicacid (A2-145): Prepared from hexahydro-2,5-methanopentalen-3a(1H)-amineHCl salt according to the procedure for A2-84. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.33-7.24 (m, 3H), 4.65-4.63 (m, 1H), 3.65-3.53 (m,2H), 2.31-2.18(m, 3H), 1.94 (br s, 4H), 1.84-1.81 (m, 2H), 1.61-1.45 (m,4H). LC-MS (condition B) m/z=440.4 (MH⁺), Retention time=2.52 min.

Synthesis of A2-152

To a solution of 3-(1-aminoethyl)adamantan-1-ol (0.25 mmol) in anhydrousDMF (2 mL) was added anhydrous Et₃N (5eq) and stirred for 10 min. Then1,1-carbonyldiimidazole was added to the mixture and stirred for 1 h atrt. INT-1 was added to the mixture and stirred overnight at rt. Themixture was diluted with ethyl acetate and the organic layer was washedwith 0.5 M HCl solution and sat. NaHCO₃ successively. Afterconcentration under reduced pressure, the crude ester was purified bysilica gel column chromatography (Eluant: 0 to 15% MeOH in DCM).(ESI-MS: 512.4 (MH⁺). The ester was dissolved in THF:H₂O (4:1, 4 mL) andtreated with 1M LiOH (0.20 mL) for 2h. The mixture was acidified to pH=2and purified by RP-HPLC to provide A2-152.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(1-(3-hydroxyadamantan-1-yl)ethyl)ureido)propanoicacid (A2-152): ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ 7.35-7.24 (m, 3H),4.72-4.65 (m, 1H), 3.74-3.4 (m, 3H), 2.20 (br s, 2H) 1.68-1.20 (m, 12H),1.01 (d, J=6.7 Hz, 3H). LC-MS (condition B) m/z=498.5 (MH⁺), Retentiontime=2.15 min.

(S)-2-(2,6-dichlorobenzamido)-3-(34(3-hydroxyadamantan-1-yl)methyl)ureido)propanoicacid (A2-153): Prepared from 3-(aminomethypadamantan-1-ol HCl saltaccording to the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) 6ppm 7.33-7.24 (m, 3H), 4.70-4.64 (m, 1H), 3.66 (d, J=4.8 Hz, 2H),2.95-2.79 (m, 4H), 2.16 (br s, 2H), 1.67-1.45 (m, 6H), 1.40-1.25 (m,6H). LC-MS (condition B) m/z=484.4 (MH⁺), Retention time=2.04 min.

(S)-3-(3-(2-(adamantan-1-yl)ethyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-154): Prepared from 2-(adamantan-1-yl)ethan-1-amine HCl saltaccording to the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.35-7.24 (m, 3H), 4.71-4.61 (m, 1H), 3.67 (br s, 2H), 3.12 (br s,2H), 1.94 (br s, 3H), 1.74-1.42 (m, 12H), 1.24 (br s, 2H). LC-MS(condition B) m/z=482.5 (MH⁺), Retention time=2.72 min.

(2S)-3-(3-(1-(adamantan-1-yl)propan-2-yl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-155): Prepared from 1-(adamantan-1-yl)propan-2-amine accordingto the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm7.35-7.25 (m, 3H), 4.63-4.58 (m, 1H), 3.85-3.5 (m, 3H), 1.91 (br s, 3H),1.75-1.40 (m, 12H), 1.2-1.06 (m, 5H). LC-MS (condition B) m/z=496.6(MH⁺), Retention time=2.76 min.

(S)-3-(3-((3-chloroadamantan-1-yl)methyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-156): Prepared from (3-chloroadamantan-1-yl)methanamine HClsalt according to the procedure for A2-152. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.35-7.25 (m, 3H), 4.66 (br s, 1H), 3.66 (d, J=4.05Hz, 2H), 2.93-2.81 (m, 2H), 2.16-1.9 (m, 6. LC-MS (condition B)m/z=502.4 (MH⁺), Retention time=2.58 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3-methyladamantan-1-yl)ureido)propanoicacid (A2-157): Prepared from 3-methyladamantan-l-amine HCl saltaccording to the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.33-7.24 (m, 3H), 4.59 (br s, 1H), 3.62-3.51 (m, 2H), 2.07 (br s,2. LC-MS (condition B) m/z=468.4 (MH⁺), Retention time=2.67 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-((lR,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)ureido)propanoicacid (A2-170) Prepared from (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (also known as(−)-Isopinocampheylamine) according to the procedure for A2-152. ¹NMR(300 MHz, CDCl₃+CD₃OD) δ ppm 7.33-7.24 (m, 3H), 4.66 (br s, 1H),3.7-3.65 (m, 3H), 2.53-2.45 (m, 1H), 2.39-2.23 (m, 1H), 1.89 (br s, 1H),1.75-1.65 (m, 2H), 1.54-1.45 (m, 1H), 1.19 (s, 3H), 1.05 (d, J=7.05 Hz,3H), 0.99 (s, 3H), 0.80 (d, J=9.7 Hz, 1H). LC-MS (condition B) m/z=456.4(MH⁺), Retention time=2.62 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)ureido)propanoicacid (A2-171): Prepared fromendo-(1R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-amine (also known asR-(+)-Bornylamine) according to the procedure for A2-152. ¹H NMR (300MHz, CDCl₃+CD₃OD) δ ppm 7.34-7.24 (m, 3H), 4.65(br s, 1H), 3.67-3.60 (m,2H), 2.31-2.23 (m, 1H), 1.68-1.45 (m, 3H), 1.4-1.05 (m, 3H), 0.90 (s,3H), 0.84 (s, 3H), 0.83-0.80 (m, 1H), 0.77 (s, 3H). LC-MS (condition B)m/z=456.4 (MH⁺), Retention time=2.61 min.

(2S)-3-(3-(bicyclo[2.2.1]heptan-2-yl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-172): Prepared from bicyclo[2.2.1]heptan-2-amine (also known asexo-2-aminonorbornane) according to the procedure for A2-152. ¹H NMR(300 MHz, CDCl₃+CD₃OD) δ ppm 7.34-7.24 (m, 3H), 4.66 (br s, 1H),3.66-3.65 (m, 2H), 3.39 (br s, 1H), 2.21-2.1 (m, 2H), 1.73-1.66 (m, 1H),1.5-1.0 (m, 7H). LC-MS (condition B) m/z=414.5 (MH⁺), Retentiontime=2.30 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-0(1R,2S,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)ureido)propanoicacid (A2-173): Prepared from((1R,2S,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanamine (alsoknown as (−)-cis-Myrtanylamine) according to the procedure for A2-152.¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.33-7.24 (m, 3H), 4.65 (br s, 1H),3.66-3.65 (m, 2H), 3.15-3.01 (m, 2H), 2.31 (br s, 1H), 2.12-2.07 (m,1H), 1.9-1.7 (m, 5H), 1.42-1.37 (m, 1H), 1.15 (s, 3H), 0.97 (s, 3H),0.85 (d, J=9.4Hz, 1H). LC-MS (condition B) m/z=456.4 (MH⁺), Retentiontime=2.64 min.

(2S)-3-(3-(bicyclo[2.2.1]heptan-2-ylmethyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-174): Prepared from bicyclo[2.2.1]heptan-2-ylmethanamine HClsalt according to the procedure for A2-152. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.33-7.24 (m, 3H), 4.65 (br s, 1H), 3.66-3.65 (m,2H), 3.11-2.95 (m, 2H), 1.8-1.2 (m, 10H), 0.98-0.92 (m, 1H). LC-MS(condition B) m/z=442.4 (MW),

Retention time=2.55 min.

(2S)-3-(3-((bicyclo[2.2.2]octan-2-yl)methypureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-175): Prepared from bicyclo[2.2.2]octan-2-yl)methanamine HClsalt according to the procedure for A2-152. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.33-7.24 (m, 3H), 4.67 (br s, 1H), 3.68-3.65 (m,2H), 3.19-3.12 (m, 1H), 3.1-2.85 (m, 1H), 2.14 (br s, 2H), 2.00-1.85 (m,1H), 1.73-1.64 (m, 1H), 1.6-0.9 (m, 8H), 0.6-0.57 (m, 1H). LC-MS(condition B) m/z=428.5 (MH⁺), Retention time=2.48 min.

(2S)-3-(3-(1-((1 S,4R)-bicyclo [2.2.1]heptan-2-yl)ethyl)ureido)-2-(2,6-dichlorobrenzamido)propanoic acid(A2-176): Prepared from 1-bicyclo[2.2.1]hept-2-ylethyl)amine accordingto the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm7.33-7.24 (m, 3H), 4.63 (br s, 1H), 3.66-3.57 (m, 2H), 3.38-3.2 (m, 1H),2.18-2.06 (m, 2H), 1.5-0.9 (m, 12H). LC-MS (condition B) m/z=442.6(MH⁺), Retention time=2.58 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(spiro[2.51]octan-1-ylmethyl)ureido)propanoicacid (A2-177): Prepared from spiro[2.5]octan-1-ylmethanamine HCl saltaccording to the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) 6ppm 7.3-7.18 (m, 3H), 4.64 (br s, 1H), 3.66-3.58 (m, 2H), 3.08-2.98 (m,2H), 1.5-1.2 (m, 10H), 1.1-1.0 (m, 1H), 0.7-0.55 (m, 1H), 0.47-0.3 (m,1H). LC-MS (condition B) m/z=442.4 (ME1⁺), Retention time=2.57 min

(S)-2-(2,6-dichlorobenzamido)-3-(3-(spiro[3.3]heptan-2-ylmethyl)ureido)propanoicacid (A2-178): Prepared from spiro[3.3]heptan-2-ylmethanamine HCl saltaccording to the procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δppm 7.35-7.2 (m, 3H), 4.65 (br s, 1H), 3.66-3.62 (m, 2H), 3.06-3.04 (m,2H), 2.25-2.15 (m, 1H), 2.1-1.9 (m, 4H), 1.9-1.7 (m, 4H), 1.63-1.5 (m,2H). LC-MS (condition B) m/z=428.4 (MH⁺), Retention time=2.53 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(spiro[5.5]undecan-3-yl)ureido)propanoicacid (A2-179): Prepared from spiro[5.5]undecan-3-amine HCl saltaccording to the procedure for A2-152. ¹1-INMR (300 MHz, CDCl₃+CD₃OD) δppm 7.32-7.25 (m, 3H), 4.63 (br s, 1H), 3.65-3.55 (m, 2H), 3.38 (br s,1H), 1.7-1.5 (m, 4H), 1.5-1.05 (m, 16H). LC-MS (condition B) m/z=470.5(MH⁺), Retention time=2.69 min

(S)-2-(2,6-dichlorobenzamido)-3-(3-(spiro[adamantane-2,1′-cyclohexan]-4′-yl)ureido)propanoicacid (A2-180): Prepared from spiro[adamantane-2,1′-cyclohexan]-4′-amineHCl salt according to the procedure for A2-152. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.33-7.25 (m, 3H), 4.66 (br s, 1H), 3.67-3.63 (m,2H), 3.47-3.33 (br s, 1H), 2.17-1.9 (m, 5H), 1.81 (br s, 3H), 1.66 (brs, 4H), 1.58-1.43 (m, 4H), 1.3-1.0 (m, 6H). LC-MS (condition B)m/z=522.4 (MH⁺), Retention time=2.80 min.

(25)-2-(2,6-dichlorobenzamido)-3-(3-(tricyclo [4.3.1.13,8]undecan-3-yl)ureido)propanoic acid (A2-181): Prepared fromtricyclo[4.3.1.1^(3,8)]undecan-3-amine according to the procedure forA2-152. ¹EINMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.33-7.25 (m, 3H), 4.60 (brs, 1H), 3.62-3.54 (m, 2H), 2.1-1.6 (m, 13H), 1.6-1.4 (m, 4H). LC-MS(condition B) m/z=468.4 (MH⁺), Retention time=2.66 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(2-phenylpropan-2-yl)ureido)propanoicacid (A2-191) Prepared from 2-phenylpropan-2-amine according to theprocedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.4-7.1 (m,8H), 4.6-4.55 (m, 1H), 3.60-3.57 (m, 1H), 1.62 (s, 3H), 1.59 (s, 3H).LC-MS (condition B) m/z=438.4 (MH⁺), Retention time=2.09 min

(2S)-3-(3-(chroman-4-yl)ureido)-2-(2,6-dichlorobenzamido)propanoic acid(A2-192) Prepared from chroman-4-amine according to the procedure forA2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.35-7.1 (m, 5H), 6.88 (t,J=7.2Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.89-4.85 (m, 1H), 4.70 (t, J=5.8Hz, 1H), 4.25-4.11 (m, 2H), 3.73-3.6 (m, 2H), 2.2-1.9 (m, 2H). LC-MS(condition B) m/z=452.3 (MH⁺), Retention time=2.09 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3,5-dimethylbenzyl)ureido)propanoicacid (A2-193) Prepared from (3,5-dimethylphenyl)methanamine according tothe procedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.35-7.2(m, 3H), 6.87 (s, 3H), 4.69 (t, J=5.2Hz, 1H), 4.29-4.17(m, 2H), 3.69 (d,J=4.9Hz, 1H), 2.27 (s, 6H). LC-MS (condition D) m/z=438.5 (MH⁺),Retention time=2.96 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)propanoicacid (A2-194) Prepared from 4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-l-amine according to the procedure for A2-152. ¹H NMR (300 MHz,CDCl₃+CD₃OD) δ ppm 7.35-7.2 (m, 3H),7.2-6.97 (m, 4H, 4.57 (br s, 1H),3.7-3.4 (m, 2H), 2.9-2.7 (m, 2H), 2.48-2.46 (m, 1H), 1.83-1.76 (m, 3H),1.56 (d, J=4.5Hz, 3H). LC-MS (condition D) m/z=438.5 (MH⁺), Retentiontime=2.96 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(naphthalen-2-ylmethyl)ureido)propanoicacid (A2-202) Prepared from naphthalen-2-ylmethanamine according to theprocedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.82-7.77 (m,3H), 7.71 (br s, 1H), 7.47-7.27 (m, 6H), 4.71 (t, J=5.6Hz, 1H), 4.52-4.4(m, 2H), 3.74-3.71 (m, 2H). LC-MS (condition D) m/z=460.3 (MH⁺),Retention time=2.90 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(naphthalen-1-ylmethyl)ureido)propanoicacid (A2-203) Prepared from naphthalen-1-ylmethanamine according to theprocedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 8.01 (d, 7.7Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.56-7.2 (m,7H), 4.84-4.68 (m, 3H), 3.73-3.71 (m, 2H). LC-MS (condition D) m/z=460.5(MH⁺), Retention time=2.89 min.

(S)-3-(3-(benzofuran-3-ylmethyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (A2-204) Prepared from benzofuran-3-ylmethanamine according to theprocedure for A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.62-7.55 (m,2H), 7.45 (d, J=7.9Hz, 1H), 7.32-7.2 (m, 4H), 4.70 (t, J=5.2 Hz, 1H),4.5-4.3 (m, 2H), 3.72-3.68 (m, 2H)hZ4-4.68 (m, 3H), 3.73-3,71 (m, 2H).LC-MS (condition D) m/z=450.3 (MH⁺), Retention time=2.80 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)ureido)propanoicacid (A2-207) Prepared from6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine according to the procedurefor A2-152. ¹H NMR (300 MHz, CDCl₃+CD₃OD) δ ppm 7.3-7.05 (m, 7H), 4.88(br s, 1H), 4.7-4.65 (m, 1H), 3.69-3.67 (m, 2H), 2.85-2.83 (m, 2H),2.0-1.5 (m, 6H). LC-MS (condition D) m/z=464.3 (MH⁺), Retentiontime=2.97 min.

(2S)-2-(2,6-dichlorobenzamido)-3-(3-methyl-3-(1,2,3,4-tetrahydronaphthalen-1-yl)ureido)propanoicacid (A2-208) Prepared from N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine according to the procedure for A2-152. ¹H NMR (300 MHz,CDCl₃+CD₃OD) 6 ppm 7.35-7.2 (m, 3H),7.15-7.0 (m, 4H), 5.48 (br s,1H),4.79-4.76 (m, 1H), 3.89-3.69 (m, 2H), 2.8-2.6 (m, 2H), 2. 59 (d,J=3Hz, 3H), 2.1-19.5 (m, 2H), 1.8-1.65 (m, 2H). LC-MS (condition D)m/z=464.5 (MH⁺), Retention time=2.96 min.

Synthesis of INT-2 (on the polymer support)

a. Fmoc-Dap(Alloc) on Wang-ChemMatrix® resin: In a round bottom flasksuspend the resin in 9:1 (VN DCM/DMF) (15 mL/g of resin). In a separateflask dissolve 2 equivalent of the carboxylic acid in a minimum amountof DMF, which was added the same equivalent of HOBt and stir the mixtureuntil HOBt dissolves. Then add the solution to the resin. In anotherseparate flask dissolve 0.1 equivalent of DMAP in a minimum amount ofDMF. Add 1.0 equivalent of DIC to the resin mixture and then add theDMAP solution. Agitate the mixture with a mechanical shaker for 2-3 h atroom temperature. Add 2 equivalent of acetic anhydride and pyridine tothe reaction flask and mix an additional 30 min at room temperature toconsume the unreacted hydroxyl group on the resin. Filter the resin,wash it with DCM (x3) and dried under vacuum.

b. Removal of Fmoc group: The Fmoc amino resin (3.83 mmol/g assumed) wastreated with 20% 4-methylpiperidine in DMF (200 mL) for 5 min andrepeated once. The resin was washed with DMF (x3), DCM (x3), andMeOH(x3) and dried under vacuum.

c. Synthesis of amide: To a DCM swollen amino resin (3.83 mmol/gassumed) was added 2,6-dichloro benzoic acid (3.64 g, 19.15 mmol, 5equiv), DIPEA (6.7 mL, 38.3 mmol, 10 equiv), and HATU (7.2 g, 18.96mmol, 4.95 equiv) in DCM and shaken overnight. The resin was filteredand washed with DCM and DMF successively to give the resin.

d. Removal of Alloc group: To a DCM swollen amino resin (3.83 mmol/gassumed) was added Pd(PPh₃)₄ (89 mg, 0.077 mmol, 0.02 equiv) andMe₂NH.BH₃ (2.26 g, 38.3 mmol, 10 equiv) in DCM and shaken 15 min. Theresin was filtered and washed with DCM, repeated two times more anddried it in vacuo.

Synthesis of KZ-1-3

a. Syntheses of analogs: To a DMF swollen INT-2 on resin (0.5 g, 3.83mmol/g assumed) was added 3-phenylpropanoic acid (225 mg, 1.5 mmol, 5equiv), HCTU (638 mg, 4.95 equiv), and DIPEA (0.52 mL, 10 equiv) in DMFand shaken overnight. The resin was filtered and washed with DMF, DCM,and dried it in vacuo.

b. Cleavage: The resin was treated with a mixture of TFA:TIPS:H20(95:2.5:2.5) (10 mL) for 3h and filtered. The filtrate was concentratedunder a stream of N₂. The crude product was purified by RP-HPLC and thepurity was confirmed by LC-MS.

(S)-2-(2,6-dichlorobenzamido)-3-(3-phenethylureido)propanoic acid(KZ-1-3):. ¹H NMR (300 MHz, CDCl₃+CD₃OD, δ) 7.36-7.33 (m, 3H), 7.26-7.23(m, 2H), 7.19-7.16 (m, 3H), 4.74 (t, J=5.7 Hz, 1H), 3.72 (d, J=5.7 Hz,2H), 2.92 (t, J=7.5 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H). LC-MS (condition A)m/z=409.5 (MH⁺), Retention time=5.18 min

Synthesis of KZ-1-9

a. Syntheses of analogs: To a DMF swollen INT-2 on resin (0.5 g, 3.83mmol/g assumed) was added 1-(isocyanatomethyl)-4-methylbenzene (10equiv) and DIPEA (6 equiv) in DMF and shaken overnight. The resin wasfiltered and washed with DMF, DCM, and dried it in vacuo.

b. Cleavage: The resin was treated with a mixture ofTFA:TIPS:H₂O(95:2.5:2.5) (10mL) for 3h and filtered. The filtrate wasconcentrated under a stream of N₂. The crude product was purified byRP-HPLC and the purity was confirmed by LC-MS.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(4-methylbenzyl)ureido)propanoic acid(KZ-1-9): ¹H NMR (300 MHz, CDCl₃+CD₃OD, δ) 7.33-7.29 (m, 3H), 7.13-7.11(m, 4H), 4.65-4.63 (m, 1H), 4.29 (s, 2 H), 3.71-3.70 (m, 2H), 2.32 (s,3H). LC-MS (condition A) m/z=424.7 (MH⁺), Retention time=5.22 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-phenethylureido)propanoic acid(KZ-1-11). Prepared from (2-isocyanatoethyl)benzene according to theprocedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.34-7.25 (m,5H), 7.21-7.15 (m, 3H), 4.58-4.56 (m, 1H), 3.73-3.56 (m, 2H), 3.49-3.38(m, 2H), 2.80-2.75 (m, 2H). LC-MS (condition A) m/z=424.4 (MH⁺),Retention time=5.15 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-((R)-1-phenylethyl)ureido)propanoicacid

(KZ-1-12). Prepared from (R)-(1-isocyanatoethyl)benzene according to theprocedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.31-7.29 (m,4H), 7.27-7.23 (m, 4H), 4.71 (s, 1H), 4.60-4.56 (m, 1H), 3.73-3.62 (m,2H), 1.40 (d, J=9.0 Hz, 3H). LC-MS (condition A) m/z=424.6 (MH⁺),Retention time=5.15 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-((S)-1-phenylethyl)ureido)propanoicacid (KZ-1-13). Prepared from (S)-(1-isocyanatoethyl)benzene accordingto the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.28-7.26(m, 8H), 4.76 (s, 1H), 4.62-4.56 (m, 1H), 3.55-3.39 (m, 2H), 1.39 (d,J=6.0 Hz, 3H). LC-MS (condition A) m/z=424.5 (MH⁺), Retention time=5.14min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(2-methoxybenzyl)ureido)propanoicacid (KZ-1-14). Prepared from 1-(isocyanatomethyl)-2-methoxybenzeneaccording to the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6)7.32-7.20 (m, 5H), 6.91-6.83 (m, 2H), 4.63-4.61 (m, 1H), 4.32 (s, 2H),3.83 (s, 3H), 3.64-3.61(m, 2H). LC-MS (condition

A) m/z=440.5 (MH⁺), Retention time=5.06 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3-methoxybenzyl)ureido)propanoicacid (KZ-1-15). Prepared from 1-(isocyanatomethyl)-3-methoxybenzeneaccording to the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6)7.29-7.23 (m, 3H), 7.19-7.14 (m, 1H), 6.80-6.72 (m, 3H), 4.64-4.62 (m,1H), 4.25 (s, 2H), 3.75 (s, 3H), 3.64-3.61(m, 2H). LC-MS (condition A)m/z=440.5 (MH⁺), Retention time=4.98 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3-methylbenzyl)ureido)propanoic acid(KZ-1-16). Prepared from 1-(isocyanatomethyl)-3-methylbenzene accordingto the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.33-7.28(m, 3H), 7.20-7.15 (m, 1H), 7.05-7.03 (m, 3H), 4.68-4.66 (m, 1H), 4.29(s, 2H), 3.81-3.69 (m, 2H), 2.31 (s, 3H). LC-MS (condition A) m/z=424.4(MH⁺), Retention time=5.22 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(furan-2-ylmethypureido)propanoicacid (KZ-1-17). Prepared from 2-(isocyanatomethyl)furan according to theprocedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.38-7.31 (m,4H), 6.31 (s, 1H), 6.22 (s, 1H), 4.64-4.55 (m, 1H), 4.35 (s, 2H),3.92-3.76 (m, 2H). LC-MS (condition A) m/z=400.5 (MH⁺),

Retention time=4.65 min.

(S)-3-(3-(2-chlorobenzypureido)-2-(2,6-dichlorobenzamido)propanoic acid(KZ-1-18). Prepared from 1-chloro-2-(isocyanatomethyl)benzene accordingto the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.29-7.21(m, 5H), 7.15-7.12 (m, 2H), 4.67-4.65 (m, 1H), 4.31 (s, 2H), 3.78-3.67(m, 2H). LC-MS (condition A) m/z=444.4 (MH⁺), Retention time=5.29 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(4-methylbenzyl)ureido)propanoic acid(KZ-1-19). Prepared from 2-isocyanato-2-methylpropane according to theprocedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.36-7.33 (m,1H), 7.32-7.28 (m, 2H), 4.58-4.57 (m, 1H), 3.78-3.71 (m, 2H), 1.31 (s,9H). LC-MS (condition A) m/z=376.5 (MH⁺), Retention time=4.87 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(4-methoxybenzyl)ureido)propanoicacid (KZ-1-20). Prepared from 1-(isocyanatomethyl)-4-methoxybenzeneaccording to the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6)7.34-7.30 (m, 2H), 7.29-7.27 (m, 1H), 7.19-7.16 (m, 2H), 6.85-6.81(m,2H), 4.62-4.56 (m, 1H), 4.27 (s, 2H), 3.79 (s, 3H), 3.63-3.61 (m, 2H).LC-MS (condition A) m/z=440.4 (MH⁺), Retention time=4.94 min.

(S)-3-(3-benzylthioureido)-2-(2,6-dichlorobenzamido)propanoic acid(KZ-1-21). Prepared from (isothiocyanatomethyl)benzene according to theprocedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.29-7.28 (m,5H), 7.20-7.17 (m, 3H), 4.78-4.76 (m, 1H), 4.62 (s, 2H), 3.64-3.44 (m,2H). LC-MS (condition A) m/z=426.1 (MH⁺), Retention time=5.43 min.

(S)-3-(3-(cyclohexylmethyl)ureido)-2-(2,6-dichlorobenzamido)propanoicacid (KZ-1-22). Prepared from (isocyanatomethyl)cyclohexane according tothe procedure for

KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.33-7.28 (m, 3H), 4.65-4.64(m, 1H), 3.83-3.68 (m, 2H), 2.97-2.95 (m, 2H), 1.68-1.66 (m, 5H),1.44-1.35 (m, 1H), 1.21-1.09 (m, 3H), 0.91-0.83 (m, 2H). LC-MS(condition A) m/z=416.2 (MH⁺), Retention time=5.46 min.

(S)-3-(3-(4-bromobenzyl)ureido)-2-(2,6-dichlorobenzamido)propanoic acid(KZ-1-23). Prepared from 1-bromo-4-(isocyanatomethyl)benzene accordingto the procedure for KZ-1-9. ^(I)H NMR (300 MHz, CDCl₃+CD₃OD, 6)7.44-7.42 (m, 2H), 7.36-7.30 (m, 3H), 7.17-7.14 (m, 2H), 4.73-4.69 (m,1H), 4.27-4.25 (m, 2H), 3.72-3.66 (m, 2H). LC-MS (condition A) m/z=488.0(MH⁺), Retention time=5.42 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-phenylureido)propanoic acid(KZ-1-25). Prepared from isocyanatobenzene according to the procedurefor KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.35-7.23 (m, 7H),7.02-6.98 (m, 1H), 4.80-4.76 (m, 1H), 3.80-3.72 (m, 2H). LC-MS(condition A) m/z=396.2 (MH⁺), Retention time=4.97 min.

(S)-3-(3-(4-chlorobenzyl)ureido)-2-(2,6-dichlorobenzamido)propanoic acid(KZ-1-26). Prepared from 1-chloro-4-(isocyanatomethyl)benzene accordingto the procedure for KZ-1-9. ^(i)H NMR (300 MHz, CDCl₃+CD₃OD, 6)7.29-7.28 (m, 4H), 7.25-7.13 (m, 3H), 4.62-4.59 (m, 1H), 4.27 (s, 2H),3.80-3.76 (m, 2H). LC-MS (condition A) m/z=444.1 (MH⁺), Retentiontime=5.33 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-propylureido)propanoic acid(KZ-1-27). Prepared from 1-isocyanatopropane according to the procedurefor KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.37-7.29 (m, 3H),4.64-4.62 (m, 1H), 4.27 (s, 2H), 3.80-3.76 (m, 2H), 3.14-3.10 (m, 2H),1.55-1.46 (m, 3H), 0.91 (t, J=7.3 Hz, 3H). LC-MS (condition A) m/z=362.0(MH⁺), Retention time=4.46 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(4-(trifluoromethyl)benzyl)ureido)propanoicacid (KZ-1-30). Prepared from1-(isocyanatomethyl)-4-(trifluoromethyl)benzene according to theprocedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.63-7.54 (m,2H), 7.42-7.33 (m, 5H), 4.69-4.64 (m, 1H), 4.37 (s, 2H), 3.44-3.35 (m,2H). LC-MS (condition A) m/z=477.9 (MH⁺), Retention time=5.52 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(3,5-difluorobenzyl)ureido)propanoicacid

(KZ-1-32). Prepared from 1,3-difluoro-5-isocyanatobenzene according tothe procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.30-7.21 (m,3H), 6.77-6.75 (m, 2H), 6.66-6.60 (m, 1H), 4.68-4.64 (m, 1H), 4.26-4.25(m, 2H), 3.67-3.65 (m, 2H). LC-MS (condition A) m/z=446.1 (MH⁺),Retention time=5.17 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(2,6-difluorobenzyl)ureido)propanoicacid (KZ-1-33). Prepared from 1,3-difluoro-2-(isocyanatomethyl)benzeneaccording to the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6)7.29-7.18 (m, 4H), 6.87-6.82 (m, 2H), 4.64-4.55 (m, 1H), 4.39 (s, 2H),3.64-3.62 (m, 2H). LC-MS (condition A) m/z=446.1 (MH⁺), Retentiontime=5.00 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(thiophen-2-ylmethyl)ureido)propanoicacid (KZ-1-34). Prepared from 2-(isocyanatomethyl)thiophene according tothe procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.30-7.16 (m,4H), 6.91 (s, 2H), 4.65-4.55 (m, 1H), 4.47 (s, 2H), 3.45-3.41 (m, 2H).LC-MS (condition A) m/z=416.6 (MN⁺), Retention time=4.84 min.

(S)-3-(3-(4-aminobenzyl)ureido)-2-(2,6-dichlorobenzamido)propanoic acid(KZ-1-37). Prepared from tent-butyl(4-(isocyanatomethyl)phenyl)carbamate according to the procedure forKZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.28-7.07 (m, 7H), 4.71-4.53(m, 1H), 4.23 (s, 2H), 3.55-3.46 (m, 2H). LC-MS (condition A) m/z=425.6(MH⁺), Retention time=3.41 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(thiophen-3-ylmethyl)ureido)propanoicacid (KZ-1-38). Prepared from 3-(isocyanatomethyl)thiophene according tothe procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.33-7.25 (m,4H), 7.11 (s, 1H), 7.00-6.98 (m, 1H), 4.61-4.60 (m, 1H), 4.33 (s, 2H),3.82-3.77 (m, 2H). LC-MS (condition A) m/z =416.5 (MH⁺), Retentiontime=4.84 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-(2-methylbenzyl)ureido)propanoic acid(KZ-1-39). Prepared from 1-(isocyanatomethyl)-2-methylbenzene accordingto the procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.29-7.23(m, 3H), 7.21-7.10 (m, 4H), 4.62-4.60 (m, 1H), 4.25 (s, 2H), 3.75-3.624(m, 2H), 2.24 (s, 3H). LC-MS (condition A) m/z =424.5 (M_H⁺), Retentiontime=5.18 min.

(S)-2-(2,6-dichlorobenzamido)-3-(3-neopentylureido)propanoic acid(KZ-1-40). Prepared from 1-isocyanato-2,2-dimethylpropane according tothe procedure for KZ-1-9. ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.34-7.24 (m,3H), 4.64-4.58 (m, 1H), 3.79-3.75 (m, 2H), 2.98-2.88 (m, 2H), 0.86 (s,9H). LC-MS (condition A) m/z=390.5 (MH⁺), Retention time=5.02 min.

Syntheses of KZ-1-80

Boc-Dap-OMe (2 g, 9.1 mmol) was treated with 4-Nitrophenyl chloroformate(1.5 equiv) and K₂CO₃ (2 equiv) in DCM at room temperature. The reactionmixture was stirred over 2 hours, dried in vacuo and purified by FlashColumn Chromatography (30% Ethyl acetate in hexanes). To thenitrophenylcarbamate was added (R)-1-amino indane hydrochloride (1.1equiv) and DIPEA (2 equiv) in DMF and reacted until the startingmaterial was consumed (monitored by TLC). The volatiles were removed invacuo and the residue was purified by Flash Column Chromatography (50%Ethyl acetate in hexanes). To this amine (250 mg) was added 4M HCl indioxane and stirred for 30 min. The volatiles were removed in vacuo andand the residue was dissolved in DMF. To the mixture were added2,4,6-trichlorobenzoic acid (1.1 equiv), HCTU (1.1 equiv), and DIPEA (5equiv) in DMF at room temperature and stirred overnight. The reactionmixture was dried in vacuo and the crude product was dissolved in THF (3mL) and 1M NaOH (2 mL) was added at room temperature ad stirred for 3 hand then neutralized by 1M HC1. The crude product was purified byRP-HPLC

(S)-3-(3-((S)-2,3-dihydro-1H-inden-1-yl)ureido)-2-(2,4,6-trichlorobenzamido)propanoicacid (KZ-1-80). ¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.84 (s, 1H), 7.35 (s,1H), 7.29-7.26 (m, 5H), 5.89 (s, 1H), 5.22 (s, 1H), 4.57 (s, 1H),3.92-3.90 (m, 1H), 3.56-3.52 (m, 1H), 2.94-2.83 (m, 2H), 2.59 (s, 1H),1.77(s, 1H), 0.90-0.88 (m, 1H). MS (ESI) m/z=470.3 (ME1⁺). Retentiontime (HPLC condition A) 26.7 min.

(S)-2-(2,6-dichloro-4-methylbenzamido)-3-(3-((S)-2,3-dihydro-1H-inden-1-yl)ureido)propanoicacid (KZ-1-81).

Prepared from 4-methyl-2,6-dichlorobenzoic acid according to theprocedure for KZ-1-80.

¹H NMR (300 MHz, CDCl₃+CD₃OD, 6) 7.62 (s, 1H), 7.29-7.10 (m, 6H), 6.31(s, 1H), 5.61 (s, 1H), 5.20 (s, 1H), 4.59-4.58 (m, 1H), 3.91-3.86 (m,1H), 3.61-3.57 (m, 1H), 2.93-2.80 (m, 2H), 2.58-2.52 (m, 1H), 2.34(s,3H), 1.80-1.68 (m, 1H). MS (ESI) m/z=450.5 (MH⁺). Retention time (HPLCcondition A) 26 min.

ii. Biological Data

Cell adhesion Assay: Ninety-sixwell flat-bottomed tissue culture plateswere coated with rat tail collagen I for 1 hour at 37° C. Afterincubation, wells were blocked with 1% BSA at 37° C. for 1 hour. Controlwells were filled with 1% BSA. HT1080 (human fibrosarcoma) cells (orhuman airway smooth muscle cells) were detached and resuspended inserum-free DMEM. Cells were incubated with anti-integrin alpha2 antibodycontrol or 10-fold dilutions of each compound with a startingconcentration of 10uM for 15 minutes at 4° C. before plating. The plateswere centrifuged at 10 g for 5 minutes before incubation for 1 hour at37° C. in humidified 5% CO₂. Nonadherent cells were removed bycentrifugation (top side down) at 10 g for 5 minutes. Attached cellswere stained with 0.5% crystal violet, and the wells were washed withPBS. The relative number of cells in each well was evaluated aftersolubilization in 40 μl of 2% Triton X-100 by measuring absorbance at595 nm in a microplate reader. All determinations were carried out intriplicate.

TABLE 1 IC₅₀s from HT 1080 Cell adhesion assay data: A: Below 10 μM, B:10 μM-100 μM, C: >100 μM. Compound Compound name IC_(50s) name IC_(50s)A2-26 B KZ-1-9 C A2-27 B KZ-1-37 C A2-28 C KZ-1-32 C A2-60 B KZ-1-33 CA2-29 A KZ-1-12 B A2-35 B KZ-1-13 C A2-36 B KZ-1-11 C A2-61 B KZ-1-25 CA2-38 C A2-73 C A2-37 C KZ-1-19 C A2-63 C KZ-1-40 C A2-64 C A2-70 CKZ-1-18 B A2-71 C KZ-1-39 B KZ-1-27 C KZ-1-14 B KZ-1-22 C KZ-1-16 BA2-83 B KZ-1-15 B A2-87 B KZ-1-26 C A2-84 B KZ-1-20 C A2-85 A KZ-1-30 CA2-86 B KZ-1-23 B KZ-1-21 B A2-72 C A2-154 B A2-39 B A2-155 B KZ-1-34 BA2-156 B KZ-1-38 B A2-157 B KZ-1-17 C A2-170 B KZ-1-36 C A2-171 A KZ-1-3C A2-172 A A2-123 A A2-173 B A2-124 A A2-174 B A2-125 A A2-175 B A2-126A A2-176 B A2-127 B A2-177 B A2-128 B A2-178 B A2-129 B A2-179 B A2-130A A2-180 B A2-131 B A2-181 B A2-132 B A2-144 B A2-133 B A2-145 B A2-134B A2-152 B A2-143 B A2-153 B

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What is claimed is:
 1. A compound having the formula:

wherein, R¹ is substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; L¹ is a bond or —C(O)—; R² ishydrogen or substituted or unsubstituted alkyl; R³ is hydrogen, halogen,—CX³ ₃, —CHX³ ₂,—CH₂X³, —OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —SO_(n3)R^(3D),—SO_(v3)NR^(3A)R^(3B), —NHC(O)NR^(3A)R^(3B), —N(O)_(m3,)—NR^(3A)R^(3B),—C(O)R^(3C), —C(O)—OR^(3C), —C(O)NR^(3A)R^(3B), —OR^(3D),—NR^(3A)SO₂R^(3D), —NR^(3A)C(O)R^(3C), —NR^(3A)C(O)OR^(3C),—NW^(3A)OR^(3C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl; or —OR³ isa prodrug moiety; R⁴ is hydrogen or substituted or unsubstituted alkyl;W¹ is O, S, NR⁸; W² is O, S, NR⁵; R⁵ is hydrogen or substituted orunsubstituted alkyl; L² is a bond or —C(R⁶)2—; R⁶ is hydrogen, ═NH,substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl; W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; R⁷ is hydrogen, halogen, —CX⁷₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —SO_(n7)NR^(7D),—SO_(V7)NR^(7A)R^(7B), —NHC(O)NR^(7A)R^(7B)—N(O)_(m7), —NR^(7A)R^(7B),—C(O)R^(7C), —C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —OR^(7D),—NR^(7A)SO₂R^(7D), —NR^(7A)C(O)R^(7C), —NR^(7A)C(O)OR^(7C),—NR^(7A)OR^(7C), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl; R⁸ ishydrogen or substituted or unsubstituted alkyl; R^(3A), R^(3B), R^(3C),R^(3D), R^(7A), R^(7B), R^(7C), and R^(7D) are independently hydrogen,—CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(3A) and R^(3B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(7A) andR^(7B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; each X, X³, and X⁷ areindependently —F, —Cl, —Br, or —I; n3 and n7 are independently aninteger from 0 to 3; and m3, m7, v3 and v7 are independently 1 or
 2. 2.The compound of claim 1 having the formula:

wherein, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;R²¹ is independently halogen, —CX²¹ ₃, —CHX²¹ ₂, —CH₂X²¹, —OCX²¹ ₃,—OCH₂X²¹, —OCHX²¹ ₂, —CN, —SO_(n21)R^(21D), —SO_(v21)NR^(21.A)R^(21B),—NHC(O)NR^(21A)R^(21B), —N(O)_(m21)—N R^(21A)R^(21B), —C(O)R^(21C),—C(O)—OR^(21C), —C(O)NR^(21A)R^(21B), —OR^(21D), —NR^(21A)SO₂R^(21D),—NR^(21A)C(O)R^(21C), —NR^(21A)C(O)OR^(21C), —NR^(21A)OR^(21C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; z21 is an integer from 0 to 5;R^(21A), R^(21B), R^(21C), and R^(21D) are independently p1 hydrogen,—CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(21A) and R^(21B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; each X andX²¹ are independently —F, —Cl, —Br, or —I; n21 is independently aninteger from 0 to 3; and m21 and v21 are independently 1 or
 2. 3. Thecompound of claim 1, wherein R¹ is unsubstituted C₁-C₆ alkyl.
 4. Thecompound of claim 1, wherein R¹ is

or substituted or unsubstituted C₁-C₈ alkyl; wherein, R¹⁰ isindependently halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰, —OCX¹⁰ ₃, —OCH₂X¹⁰,—OCHX¹⁰ ₂, —CN, —SO_(n10)R^(10D), —SO_(v10)NR^(10A)R^(10B),—NHC(O)NR^(10A)R^(10B), —N(O)_(m10)—NR^(10A)R^(10B), ——C(O)R^(10C),—C(O)—OR^(10C), —C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)OR^(10C), —NR^(10A)OR^(10C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; two adjacent R¹⁰ substituents may optionally be joined toform a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(10A), R^(10B), R^(10C), andR^(10D) are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(10A) and R^(16B)substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl; X and X¹⁰ are independently —F, —Cl, —Br,or —I; n10 is independently an integer from 0 to 4; m10 and v10 areindependently 1 or 2; and z10 is an integer from 0 to
 5. 5. The compoundof claim 1, wherein L² is —C(R⁶)₂—.
 6. The compound of claim 1, whereinL² is —CHR⁶—.
 7. The compound of claim 1, wherein L² is a bond.
 8. Thecompound of claim 1, wherein R⁶ is unsubstituted alkyl.
 9. The compoundof claim 1, wherein R⁶ is hydrogen.
 10. The compound of claim 1, whereinW¹ is NH.
 11. The compound of claim 1, wherein W¹ is S.
 12. The compoundof claim 1, wherein W¹ is O.
 13. The compound of claim 1, wherein W² isNH.
 14. The compound of claim 1, wherein W² is S.
 15. The compound ofclaim 1, wherein W² is O.
 16. The compound of claim 1, wherein W¹ and R⁶are joined to form a substituted or unsubstituted 5 to 6 memberedheterocycloalkyl or substituted or unsubstituted 5 to 6 memberedheteroaryl.
 17. The compound of claim 1, wherein W¹ and R⁶ are joined toform a substituted or unsubstituted 5 to 6 membered heteroaryl.
 18. Thecompound of claim 1, wherein W¹ and R⁶ are joined to form


19. The compound of claim 1, wherein R², R⁴, R⁵, and R⁸ are hydrogen.20. The compound of claim 1, wherein R³ is substituted or unsubstitutedC₁-C₆ alkyl.
 21. The compound of claim 1, wherein R³ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl.
 22. The compound of claim 1,wherein —OR³ is a prodrug moiety.
 23. The compound of claim 1, wherein—OR³ is a prodrug moiety capable of being cleaved from the remainder ofthe compound by an esterase or amidase.
 24. The compound of claim 1,wherein R³ is substituted or unsubstituted C₁-C₈ alkyl,

substituted or unsubstituted aryl, (acyloxy)alkyl,[(alkoxycarbonyl)oxy]methyl, or (oxodioxolyl)methyl.
 25. The compound ofclaim 1, wherein R³ is hydrogen.
 26. The compound of claim 1, wherein L¹is a bond.
 27. The compound of claim 1, wherein L¹ is —C(O)—.
 28. Thecompound of claim 1, wherein R⁷ is unsubstituted C₁-C₆ alkyl.
 29. Thecompound of claim 1, wherein R⁷ is unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.
 30. The compound claim 1, wherein R⁷ is substituted orunsubstituted cycloalkyl.
 31. The compound claim 1, wherein R⁷ issubstituted or unsubstituted cyclohexyl, adamantyl, tetrahydronaphthyl,dihydroindenyl, or bicyclo[3.3.1]heptanyl, 2,3-dihydro-1H-indenyl. 32.The compound of claim 1, wherein R⁷ is substituted or unsubstitutedC₇-C₁₂ fused cycloalkyl.
 33. The compound of claim 1, wherein R⁷ issubstituted or unsubstituted C₇-C₁₂ bridged cycloalkyl.
 34. The compoundof claim 1, wherein R⁷ is substituted or unsubstituted C₇-C₁₅spirocyclic cycloalkyl.
 35. The compound of claim 1, wherein

wherein z21 is an integer from 0 to
 5. 36. The compound of claim 1,wherein


37. The compound of claim 2, wherein Ring A is 5 to 6 memberedheteroaryl.
 38. The compound of claim 2, wherein Ring A is phenyl. 39.The compound of claim 2, wherein Ring A is a bicyclic C₉-C₁₀ aryl orbicyclic 8 to 10 membered heteroaryl.
 40. The compound of claim 2,wherein z21 is an integer from 1 to
 5. 41. The compound of claim 2,wherein z21 is
 0. 42. The compound of claim 1, having the formula:


43. The compound of claim 1, having the formula:


44. The compound of claim 1, having the formula:

wherein R¹ is


45. The compound of claim 44, wherein

is A)

wherein z21 is an integer from 0to 5; B)

; wherein z21 is an integer from 0 to 4; C)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; F)

wherein z21 is an integer from 0 to 2; or G)

wherein z21 is an integer from 1 to
 5. 46. The compound of claim 1,having the formula:

wherein R^(l) is


47. The compound of claim 46, wherein

is A)

wherein z21 is an integer from 0 to 5; B)

wherein z21 is an integer from 0 to 4; C)

D)

wherein R⁷ is substituted or unsubstituted cycloalkyl; E)

wherein z21 is an integer from 0 to 3; or F)

wherein z21 is an integer from 0 to
 2. 48. The compound of claim 1,having the formula:


49. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of one of claims 1 to
 48. 50. Amethod of treating asthma, the method comprising administering to asubject in need thereof an effective amount of an integrin α2β1inhibitor.
 51. The method of claim 50, wherein the α2β1 inhibitor is anucleic acid, protein, or compound.
 52. The method of claim 50, whereinthe α2β1 inhibitor is compound of one of claims 1 to
 48. 53. A method oftreating asthma, the method comprising administering to a subject inneed thereof an effective amount of a compound of one of claims 1 to 48.54. A method of treating asthma, the method comprising administering toa subject in need thereof an effective amount of a compound, or apharmaceutically, having the formula:

wherein, R¹ is substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; L′ is abond or —C(O)—; R² is hydrogen or substituted or unsubstituted alkyl; R³is hydrogen, halogen, —CX³ ₃, CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³, —OCHX³₂, —CN, —SO_(n3)R^(3D), —SO_(v3)NR^(3A)R^(3B), —NHC(O)NR^(3A)R^(3B),—N(O)_(m3), —NR^(3A)R^(3B), —C(O)R^(3C), —C(O)—OR^(3C),—C(O)NR^(3A)R^(3B), —OR^(3D), —NR^(3A)SO₂R^(3D), —NR^(3A)C(O)R^(3C),—NR^(3A)C(O)OR^(3C), —NR^(3A)OR^(3C), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl; R⁴ is hydrogen or substituted or unsubstituted alkyl; W¹ isO, S, NR⁸; W² is O, S, NR⁵; R⁵ is hydrogen or substituted orunsubstituted alkyl; L² is a bond or —CHR⁶—; R⁶ is hydrogen,═NH,substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl; W¹ and R⁶ may optionally be joined to form a substituted orunsubstituted 5 to 6 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; R⁷ is hydrogen, halogen, —CX⁷₃, —CHX⁷ ₂, —CH₂X⁷, —OCX⁷ ₃, —OCH₂X⁷, —OCHX⁷ ₂, —CN, —SO_(n7)R^(7D),—SO_(v7)NR^(7A)R^(7B), —NHC(O)NR^(7A)R^(7B), —N(O)_(m7), —NR^(7A)R^(7B),—C(O)R^(7C), —C(O)—OR^(7C), —C(O)NR^(7A)R^(7B), —NR^(7A)SO₂R^(7D),—NR^(7A)C(O)R^(7C), —NR^(7A)C(O)OR^(7C), —NR^(7A)OR^(7C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl; R⁸ is hydrogen or substituted or unsubstitutedalkyl; R^(3A), R^(3B), R^(3C), R^(3D), R^(7A), R^(7B), R^(7C), andR^(7D) are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂,—CH₂X, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(3A) and R^(3B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(7A) and R^(7B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; each X, X³, and X⁷ are independently —F, —Cl, —Br, or —I; n3and n7 are independently an integer from 0 to 3; and m3, m7, v3 and v7are independently 1 or
 2. 55. The method of claim 54, wherein R¹ is

or substituted or unsubstituted C₄-C₈ alkyl; wherein, R⁹ isindependently halogen, —CX⁹ ₃, —CHX⁹ ₂, —CH₂X⁹, —OCX⁹ ₃, —OCH₂X⁹, —OCHX⁹₂, —CN, —SO_(n9)R^(9D), —SO_(v9)NR^(9A)R^(9B), —NHC(O)NR^(9A)R^(9B),—N(O)_(m9), —NR^(9A)R^(9B), —C(O)R^(9C), —C(O)—OR^(9C),—C(O)NR^(9A)R^(9B), —OR^(9D), —NR^(9A)SO₂R^(9D),—NR^(9A)C(O)R^(9C)—NR^(9A)C(O)O R^(9C), —NR^(9A)OR^(9C), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁰ is independently halogen,—CX¹⁰ ₃, —CHX¹⁰ ₂, —CH₂X¹⁰, —OCX¹⁰ ₃, —OCH₂X¹⁰, —OCHX¹⁰ ₂, —CN,—SO_(n10)R^(10D), —SO_(v10)NR_(10A)R_(10B), —NHC(O)NR^(10A)R^(10B),—N(O)_(m10), —NR^(10A)R^(10B), —C(O)R^(10C), —C(O)—OR^(10 C),—C(O)NR^(10A)R^(10B), —OR^(10D), —NR^(10A)SO₂R^(10D),—NR^(10A)C(O)R^(10C), —NR^(10 A) C(O)OR^(10C), —NR^(10A)OR^(10C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹⁰ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C), and R^(10D)are independently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(9A) and R^(9B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(10A) and R^(10B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; X, X⁹, and X¹⁰ are independently —F, —Cl, —Br, or —I; n9 andn10 are independently an integer from 0 to 4; m9, m10, v9 and v10 areindependently 1 or 2; z9 is an integer from 0 to 5; and z10 is aninteger from 0 to
 5. 56. The method of claim 54, wherein R¹ is


57. The method of claim 54, wherein the compound is


58. The method of claim 54, wherein the compound is


59. The method of claim 54, wherein R⁷ is substituted or unsubstitutedcycloalkyl.
 60. The method of claim 54, wherein R⁷ is substituted orunsubstituted cyclohexyl, adamantly, tetrahydronaphthyl, dihydroindenyl,or bicyclo[3.3.1]heptanyl, 2,3-dihydro-1H-indenyl.
 61. The method ofclaim 54, wherein

wherein z21 is an integer from 0 to
 5. 62. The method of claim 54,wherein


63. The method of claim 54, wherein Ring A is a bicyclic C₉-C₁₀ aryl orbicyclic 8 to 10 membered heteroaryl.